Chemical Process

ABSTRACT

The present invention relates to chemical processes for the manufacture of certain quinazoline derivatives, or pharmaceutically acceptable salts thereof. The invention also relates to processes for the manufacture of certain intermediates useful in the manufacture of the quinazoline derivatives and to processes for the manufacture of the quinazoline derivatives utilising said intermediates. In particular, the present invention relates to chemical processes and intermediates useful in the manufacture of the compound 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline.

The present invention relates to chemical processes for the manufactureof certain quinazoline derivatives, or pharmaceutically acceptable saltsthereof. The invention also relates to processes for the manufacture ofcertain intermediates useful in the manufacture of the quinazolinederivatives and to processes for the manufacture of the quinazolinederivatives utilising said intermediates.

In particular, the present invention relates to chemical processes andintermediates useful in the manufacture of the compound4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline.This compound falls within the broad disclosure of WO 98/13354 and isexemplified in WO 01/32651, in Examples 2a, 2b and 2c.

The compound4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazolineis described herein by way of the Formula I:

and as ZD6474, the code number by which the compound is known. Thecompound ZD6474 is also known as Vandetanib and as Zactima™.

Normal angiogenesis plays an important role in a variety of processesincluding embryonic development, wound healing and several components offemale reproductive function. Undesirable or pathological angiogenesishas been associated with disease states including diabetic retinopathy,psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma andhaemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman,1995, Nature Medicine 1: 27-31). Alteration of vascular permeability isthought to play a role in both normal and pathological physiologicalprocesses (Cullinan-Bove et al, 1993, Endocrinology 133: 829-837; Sengeret al, 1993, Cancer and Metastasis Reviews, 12: 303-324). Severalpolypeptides with in vitro endothelial cell growth promoting activityhave been identified including, acidic and basic fibroblast growthfactors (aFGF & bFGF) and vascular endothelial growth factor (VEGF). Byvirtue of the restricted expression of its receptors, the growth factoractivity of VEGF, in contrast to that of the FGFs, is relativelyspecific towards endothelial cells. Recent evidence indicates that VEGFis an important stimulator of both normal and pathological angiogenesis(Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995,Breast Cancer Research and Treatment, 36:139-155) and vascularpermeability (Connolly et al, 1989, J. Biol. Chem. 264: 20017-20024).Antagonism of VEGF action by sequestration of VEGF with antibody canresult in inhibition of tumour growth (Kim et al, 1993, Nature 362:841-844).

Receptor tyrosine kinases (RTKs) are important in the transmission ofbiochemical signals across the plasma membrane of cells. Thesetransmembrane molecules characteristically consist of an extracellularligand-binding domain connected through a segment in the plasma membraneto an intracellular tyrosine kinase domain. Binding of ligand to thereceptor results in stimulation of the receptor-associated tyrosinekinase activity which leads to phosphorylation of tyrosine residues onboth the receptor and other intracellular molecules. These changes intyrosine phosphorylation initiate a signalling cascade leading to avariety of cellular responses. To date, at least nineteen distinct RTKsubfamilies, defined by amino acid sequence homology, have beenidentified. One of these subfamilies is presently comprised by thefins-like tyrosine kinase receptor, Flt-1 (also referred to as VEGFR-1),the kinase insert domain-containing receptor, KDR (also referred to asVEGFR-2 or Flk-1), and another fins-like tyrosine kinase receptor,Flt-4. Two of these related RTKs, Flt-1 and KDR, have been shown to bindVEGF with high affinity (De Vries et al, 1992, Science 255: 989-991;Terman et al, 1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579-1586).Binding of VEGF to these receptors expressed in heterologous cells hasbeen associated with changes in the tyrosine phosphorylation status ofcellular proteins and calcium fluxes.

VEGF is a key stimulus for vasculogenesis and angiogenesis. Thiscytokine induces a vascular sprouting phenotype by inducing endothelialcell proliferation, protease expression and migration, and subsequentorganisation of cells to form a capillary tube (Keck, P. J., Hauser, S.D., Krivi, G., Sanzo, K., Warren, T., Feder, J., and Connolly, D. T.,Science (Washington D.C.), 246: 1309-1312, 1989; Lamoreaux, W. J.,Fitzgerald, M. E., Reiner, A., Hasty, K. A., and Charles, S. T.,Microvasc. Res., 55: 29-42, 1998; Pepper, M. S., Montesano, R.,Mandroita, S. J., Orci, L. and Vassalli, J. D., Enzyme Protein, 49:138-162, 1996). In addition, VEGF induces significant vascularpermeability (Dvorak, H. F., Detmar, M., Claffey, K. P., Nagy, J. A.,van de Water, L., and Senger, D. R., (Int. Arch. Allergy Immunol., 107:233-235, 1995; Bates, D. O., Heald, R. I., Curry, F. E. and Williams, B.J. Physiol. (Lond.), 533: 263-272, 2001), promoting formation of ahyper-permeable, immature vascular network which is characteristic ofpathological angiogenesis.

It has been shown that activation of KDR alone is sufficient to promoteall of the major phenotypic responses to VEGF, including endothelialcell proliferation, migration, and survival, and the induction ofvascular permeability (Meyer, M., Clauss, M., Lepple-Wienhues, A.,Waltenberger, J., Augustin, H. G., Ziche, M., Lanz, C., Büttner, M.,Rziha, H-J., and Dehio, C., EMBO J., 18: 363-374, 1999; Zeng, H.,Sanyal, S. and Mukhopadhyay, D., J. Biol. Chem., 276: 32714-32719, 2001;Gille, H., Kowalski, J., Li, B., LeCouter, J., Moffat, B, Zioncheck, T.F., Pelletier, N. and Ferrara, N., J. Biol. Chem., 276: 3222-3230,2001).

ZD6474 is a potent inhibitor of VEGF RTK and also has some activityagainst epidermal growth factor (EGF) RTK. ZD6474 inhibits the effectsof VEGF and is of interest for its antiangiogenic and/or vascularpermeability effects. Angiogenesis and/or an increase in vascularpermeability is present in a wide range of disease states includingcancer (including leukaemia, multiple myeloma and lymphoma), diabetes,psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acuteand chronic nephropathies, atheroma, arterial restenosis, autoimmunediseases, acute inflammation, excessive scar formation and adhesions,lymphoedema, endometriosis, dysfunctional uterine bleeding and oculardiseases with retinal vessel proliferation including age-related maculardegeneration. ZD6474 has been shown to elicit broad-spectrum anti-tumouractivity in a range of models following once-daily oral administration(Wedge S. R., Ogilvie D. J., Dukes M. et al, Proc. Am. Assoc. Canc. Res.2001; 42: abstract 3126).

WO 98/13354 discloses several possible routes for preparing 4-anilinoquinazoline compounds. However, there is no specific disclosure in WO98/13354 of a process for preparing a compound of the Formula I.

WO 98/10767 also discloses several possible routes for preparing4-anilino quinazoline compounds. However, there is no specificdisclosure in WO 98/10767 of a process for preparing a compound of theFormula I.

WO 01/32651 discloses several alternative routes for preparing acompound of the Formula I.

The route that is disclosed in Example 2a of WO 01/32651 involves thereaction of the compound4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazolinewith aqueous formaldehyde, followed by sodium cyanoborohydride in asolvent mixture of tetrahydrofuran and methanol. The product is purifiedby chromatography and isolated as the free base. The free base is thenconverted to the hydrochloride salt by reaction with hydrogen chloridein a solvent mixture of methylene chloride and methanol.

The route that is disclosed in Example 2b of WO 01/32651 involves thereaction of the compound4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)quinazolinewith aqueous formaldehyde in formic acid, followed by reaction withsodium hydroxide in water and extraction of the product with ethylacetate. The product is in the form of the free base.

The route that is disclosed in Example 2c of WO 01/32651 involves thereaction of the compound4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline with4-bromo-2-fluoroaniline and hydrogen chloride in isopropanol. Theproduct that is isolated is in the form of the hydrochloride salt. In anNMR experiment, the hydrochloride salt is dissolved in dimethylsulfoxideand converted to the free base by adding solid potassium carbonate. Thefree base is then converted to the trifluoroacetate salt by addingtrifluoroacetic acid. In another experiment, the hydrochloride salt issuspended in methylene chloride and washed with saturated sodiumhydrogen carbonate to provide the free base.

WO 01/32651 also discloses routes for preparing the starting materialsthat are used in Examples 2a, 2b and 2c, such as the compounds4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline,4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)quinazolineand 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline.Several of these routes are discussed in more detail below.

The routes described in WO 01/32651 for preparing ZD6474 (as thehydrochloride salt or the free base) are also described and/orreferenced in publications relating to combination therapies includingZD6474, such as WO 03/039551, WO 2004/014383, WO 2004/014426, WO2004/032937, WO 2004/071397 and WO 2005/004870.

The existing routes for preparing the compound of the Formula I aresatisfactory for the synthesis of relatively small amounts of thecompound. However, the routes involve linear rather than convergentsynthesis, requiring the use of multiple purification steps and theisolation of a substantial number of intermediates. As such, the overallyield of the synthesis is not high. There is, therefore, a need for amore efficient synthesis of the compound of the Formula I suitable foruse to make larger quantities of that compound. There is also a need formore efficient syntheses of the intermediate compounds useful in thesynthesis of the compound of the Formula I for use to make largerquantities of those intermediate compounds.

Preferably, the new syntheses should minimise the number of intermediatecompounds that need to be isolated and should not involve costly andtime-consuming purification procedures. Additionally, the new synthesesshould form consistently high quality compounds, in particular so as toform a high quality compound of the Formula I to satisfy the high purityrequirements of a pharmaceutical product. The new syntheses should alsouse procedures and reagents that can safely be used in a manufacturingplant and that meet environmental guidelines.

According to the present invention, we now provide improved processesfor the manufacture of ZD6474, the compound of the Formula I.

According to the present invention, processes are also provided for themanufacture of key intermediate compounds that may be used in themanufacture of ZD6474.

The new processes are advantageous in that they allow the compounds tobe made in high quality and high yield on a larger scale. The processesallow a substantial reduction in the number of intermediate compoundsthat must be isolated and, in general, are more convergent than theprevious routes. Such changes provide significant advantages of time andcost.

For the avoidance of doubt, the term “ZD6474” as used hereinafter refersto the ZD6474 free base, unless otherwise stated.

A key intermediate that may be used in the preparation of ZD6474 is acompound of Formula IIa

Wherein R is a suitable sulphonate ester such as mesylate, esylate,besylate or tosylate.

In a further embodiment the compound of Formula IIa is1-(tert-butoxycarbonyl)-4-(4-methylphenylsulfonyloxymethyl)piperidine,the compound of the Formula II:

Example 2 of WO 01/32651 discloses a route for the preparation of acompound of the Formula II. The route involves the reaction of ethyl4-piperidinecarboxylate with di-tert-butyl dicarbonate in an ethylacetate solvent to provide ethyl4-(1-(tert-butoxycarbonyl)piperidine)carboxylate, which is isolated. Theethyl 4-(1-(tert-butoxycarbonyl)piperidine)carboxylate is then reactedwith lithium aluminium hydride in tetrahydrofuran to provide1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine, which is isolated.The 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine is then reactedwith 1,4-diazabicyclo[2.2.2]octane and toluene sulfonyl chloride in atert-butyl methyl ether solvent to provide the compound of the FormulaII.

EP-A-0317997 discloses a route for the preparation of a compound of theFormula II. The route involves the reaction of 4-carboxypiperidine (alsoknown as isonipecotic acid) with sodium carbonate and di-tert-butyldicarbonate in a water solvent to provide4-carboxy-piperidine-1-carboxylic acid tert-butyl ester, which isisolated. The 4-carboxy-piperidine-1-carboxylic acid tert-butyl ester isthen reacted with borane in a tetrahydrofuran solvent to provide thecompound of the Formula II.

WO 94/27965 discloses a route for the preparation of a compound of theFormula II. The route involves the reaction of 4-hydroxymethylpiperidinewith di-tert-butyl dicarbonate in a tetrahydrofuran solvent to providetert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate, which is isolatedas an oil. The 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine is thenreacted with toluene sulfonyl chloride and pyridine to provide thecompound of the Formula II.

The routes disclosed in the prior art documents for the preparation of acompound of the Formula II are satisfactory for the synthesis ofrelatively small amounts of the compound. However, they all require eachof the intermediates to be isolated and, therefore, include multipleisolation and/or purification steps. This results in a satisfactoryoverall yield of the compound of the Formula II on the small scale used.However, the routes disclosed in the prior art documents are unsuitablefor use on a manufacturing scale because they include multiple isolationand/or purification steps, which cannot be conducted efficiently on amanufacturing scale. In particular, the routes disclosed in the priorart documents are unsuitable for use in the manufacture of a high puritypharmaceutical product.

There is, therefore, a need for a more efficient synthesis of a compoundof the Formula II suitable for use to make larger quantities of thatcompound. Preferably, the new synthesis should not involve costly andtime-consuming isolation and/or purification procedures. Thus, the newsynthesis should reduce the number of isolation and/or purificationprocedures required, thereby reducing costs and time of manufacture.Preferably, the new synthesis should minimise the number of solventsused throughout the process, which improves environmental performanceand provides the opportunity for solvent recovery. Preferably, the newsynthesis should also provide a robust and reliable method of isolatingthe compound of the Formula II and consistently should provide highquality compound of the Formula II, for example so as to satisfy theregulatory requirements for the introduction of starting materials intothe production of pharmaceutical products.

According to a first aspect of the present invention, there is provideda process for the manufacture of a compound of the Formula IIa from a(C1-C6)alkyl-4-piperidinecarboxylate compound of the Formula III:

which process comprises the steps of:

-   (a) reacting the (C1-C6)alkyl-4-piperidinecarboxylate compound of    the Formula III with di-tert-butyl dicarbonate in the presence of    toluene or xylene to form a first mixture comprising toluene or    xylene, tert-butanol and a compound of the Formula IV:

-   (b) substantially removing the tert-butanol from the first mixture;-   (c) reacting the compound of the Formula IV with a suitable reducing    agent in situ in the presence of toluene or xylene to form a second    mixture comprising toluene, reduction by-products including alcohol    by-products and a compound of the Formula V:

-   (d) substantially removing the alcohol by-products from the second    mixture; and-   (e) reacting the compound of the Formula V with a suitable    sulphonating agent in situ to form a sulphonate ester in the    presence of a suitable base and toluene to form the compound of the    Formula IIa.

wherein R is a suitable sulphonate ester such as mesylate, esylate,besylate or tosylate. In one embodiment the sulphonating agent is tosylchloride.

For avoidance of doubt the term ‘in situ’ means that the reaction wasperformed without isolation of the reactants from the previous processstep.

The process of the first aspect of the present invention is advantageousin that it allows a compound of the Formula IIa to be made in highquality and high yield on a larger scale. Typically, each of the stepsof the process of the first aspect of the present invention proceeds ingreater than 95% yield.

All steps of the process of the first aspect of the present inventionare conducted in toluene or xylene as the solvent. In another embodimentall the steps of the first aspect of the present invention are conductedin toluene. This allows the process to be conducted as a continuousprocess without isolation and/or purification of the intermediatecompounds of the Formulae IV and V. This significantly reduces the timeand cost of manufacturing the compound of the Formula IIa on a largerscale. The use of a single solvent such as toluene or xylene may alsoallow for solvent recycling, which increases the efficiency of theprocess and provides environmental benefits. The use of toluene orxylene as the solvent also allows for the efficient and convenientremoval of reactive by-products (such as alcohols), for example bydistillation. The presence of such reactive by-products could lead toimpurities in the compound of the Formula IIa if not removed at theappropriate time.

Additionally, the use of toluene or xylene as the solvent in the processof the first aspect of the present invention allows for the convenientisolation of the compound of the Formula IIa by crystallisation. Thecompound of the Formula IIa may, for example, be isolated in greaterthan 99.5% purity by crystallisation directly from the reaction mixturewithout the need for further purification. This is advantageous, forexample when the compound of the Formula IIa is to be introduced at alate stage into the production of a pharmaceutical product, for examplea compound of the Formula I, because it minimises the risk of impuritiesbeing introduced into the pharmaceutical product.

Step (a) of the process uses a (C1-C6)alkyl-4-piperidinecarboxylatecompound of the Formula III, particularly a(C1-C4)alkyl-4-piperidinecarboxylate compound of the Formula III. Inparticular, a suitable (C1-C6)alkyl-4-piperidinecarboxylate compound ofthe Formula III that may be used in step (a) may, for example, be ethyl4-piperidinecarboxylate. Another name for ethyl 4-piperidine carboxylateis ethyl isonipecotate.

The reaction of step (a) is carried out at a temperature in the range,for example, of from 0 to 45° C., conveniently in the range of from 15to 35° C., more conveniently in the range of from 25 to 30° C.

The (C1-C6)alkyl-4-piperidinecarboxylate compounds of the Formula IIIand the di-tert-butyl dicarbonate starting material used in step (a) ofthe process are commercially available or can be prepared usingconventional methods. For example, the(C1-C6)alkyl-4-piperidinecarboxylate compounds of the Formula III may beprepared as described in Japanese patent application number JP 03002162A2.

The tert-butanol that is formed in step (a) is a by-product of thereaction between the (C1-C6)alkyl-4-piperidinecarboxylate compound ofthe Formula III and the di-tert-butyl dicarbonate. In the process of thepresent invention, this by-product is easily and convenientlysubstantially removed from the reaction mixture, for example bydistillation in step (b).

It is advantageous to substantially remove the tert-butanol by-productfrom the reaction mixture, for example by distillation in step (b)because any tert-butanol by-product that is not removed is likely toreact with the reducing agent in step (c), thereby reducing the amountof the reducing agent available for the desired reaction with thecompound of the Formula IV. Thus, removal of the tert-butanol by-productin step (b) allows for the correct stoichiometry of the reagents in step(c) of the process and, therefore, a more efficient reaction in thatstep. This is turn provides a high yield and purity of the compound ofthe Formula V in step (c).

By the term “substantially removed” we mean that at least 85% of thetert-butanol by-product that is formed in step (a) is removed, forexample by distillation. Typically, the distillation is conducted untilan internal temperature in the range of between 102 to 112° C. isachieved. The distillation in step (b) is conveniently conducted ateither atmospheric or partially reduced pressure.

Suitable reducing agents for use in step (c) include sodiumbis(2-methoxyethoxy)aluminium hydride, lithium aluminium hydride anddiisobutylaluminium hydride. More particularly, the reducing agent usedin step (c) is sodium bis(2-methoxyethoxy)aluminium hydride.

The reaction of step (c) is carried out at a temperature in the range,for example, of from 20 to 55° C., conveniently in the range of from 30to 50° C., more conveniently in the range of from 35 to 45° C.

As the skilled person would appreciate, the reaction of step (c)typically provides reduction by-products in addition to the desiredcompound of the Formula V. The reduction by-products include alcoholby-products. The alcohol by-products originate from the —O-(C1-C6)alkylportion of the ester group in the compound of the Formula IV and mayalso originate from the reducing agent. For example, when the compoundof the Formula IV is ethyl4-(1-tert-butoxycarbonyl)piperidine)carboxylate and the reducing agentused in step (c) is sodium bis(2-methoxyethoxy)aluminium hydride,typical reduction by-products include aluminium salts and alcoholby-products such as ethanol and 2-methoxyethanol. The alcoholby-products are easily and conveniently substantially removed from thereaction mixture for example by distillation in step (d).

It is advantageous to substantially remove the alcohol by-products instep (d) because any such by-products that are not removed are likely toreact with the sulphonating agent in step (e), thereby creatingimpurities that could contaminate the desired product and reducing theamount of sulphonating agent available for the desired reaction with thecompound of the Formula V. Thus, removal of the alcohol by-productsallows for the correct stoichiometry of the reagents in step (e) of theprocess and, therefore, a more efficient reaction in that step. This isturn provides a high yield and purity of the compound of the Formula IIin step (e).

By the term “substantially removed” we mean that at least 98% of thealcohol by-products that are formed in step (c) are removed for exampleby distillation. Typically, the distillation is conducted until aninternal temperature in the range of from between 102° C. to 112° C. isachieved. The distillation in step (d) is conveniently conducted ateither atmospheric or partially reduced pressure.

The distillation in step (d) also typically substantially removes anywater that is present. This again allows for the correct stoichiometryof the reagents in step (e) of the process because any water that is notremoved is likely to react with the sulphonating agent in step (e),thereby reducing the amount of the sulphonating agent available for thedesired reaction with the compound of the Formula V. By the term“substantially removed” we mean that less than 20 mol % of water remainsafter the distillation.

As the skilled person would appreciate, it is typically necessary toquench the reaction mixture in step (c) to remove any unreacted reducingagent that is present before the reaction in step (e) is conducted.Typically, the quench step also removes some of the reductionby-products listed above, for example the aluminium salts and some, butnot all, of the alcohol by-products. Suitable quenching agents may ingeneral be chosen from any agent that is described in the literatureand/or that is known to the skilled person. For example, when thereducing agent used in step (c) is sodium bis(2-methoxyethoxy)aluminiumhydride, the quenching agent typically may be an aqueous solution ofpotassium sodium tartrate (also known as Rochelle salt). Typically, theresulting aqueous phase (containing the quenched reducing agent) is thenremoved by separation. The quench step is conducted before thedistillation in step (d).

A suitable base for use in step (e) is a tertiary amine base, forexample triethylenediamine.

The reaction of step (e) is carried out at a temperature in the range,for example, of from 15 to 45° C., more conveniently in the range offrom 25 to 35° C.

As the skilled person would appreciate, it is typically necessary toquench the reaction mixture in step (e) to remove any unreactedsulphonating agent that is present. Suitable quenching agents may ingeneral be chosen from any agent that is described in the literatureand/or that is known to the skilled person. For example, a suitablequenching agent may be a base such as sodium hydroxide or potassiumcarbonate.

In one aspect, the process for the manufacture of a compound of theFormula II may further include the step (f) of isolating and/orpurifying the compound of the Formula II. The step (f) may comprise anysuitable steps or procedures for isolating the desired product that aredescribed in the literature and/or that are known to the skilled person.Particular steps that would be of use would provide high quality andhigh purity product. For example, the step (f) may comprise the steps ofwashing the compound of the Formula II with water and/or aqueous citricacid. The step (f) may, for example, also comprise crystallisation usinga suitable solvent system. An example of a suitable solvent system is asolvent system comprising toluene and isohexane, which provides acompound of the Formula II in a high purity, typically in a purity ofgreater than 98%, conveniently greater than 99.5%, and in a high yield,typically in a yield of greater than 80%, conveniently greater than 85%.As a skilled person would appreciate, the step (f) may also comprise thestep of temperature cycling (also referred to as “Östwald ripening”) thecompound of the Formula II, so as to improve the physical form of theproduct, if necessary.

Another key intermediate that may be used in the preparation of ZD6474is a protected derivative of7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline, the compoundof the Formula VI:

wherein R¹ is an acid labile protecting group, such as benzyl,substituted benzyl, tert-butyl, allyl or methoxyethoxymethyl.

Example 2 of WO 01/32651 and Example 24 of WO 97/32856 each disclose aroute for the preparation of a hydrochloride salt of a compound of theFormula VI wherein R¹ is benzyl. The route involves the reaction of ahydrochloride salt of 7-benzyloxy-4-chloro-6-methoxyquinazoline with4-bromo-2-fluoroaniline in a 2-propanol solvent to provide thehydrochloride salt of the compound of the Formula VI, which is isolated.It is stated in Example 2 of WO 01/32651 that the hydrochloride salt of7-benzyloxy-4-chloro-6-methoxyquinazoline is prepared according toExample 1 of WO 97/22596. In Example 1 of WO 97/22596, the hydrochloridesalt of 7-benzyloxy-4-chloro-6-methoxyquinazoline is prepared by thereaction of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one withthionyl chloride in a N,N-dimethylformamide solvent. The same processfor the preparation of the hydrochloride salt of7-benzyloxy-4-chloro-6-methoxyquinazoline is disclosed in Example 4 ofWO 97/32856.

WO 98/10767 discloses a route for the preparation of 6,7-disubstituted4-anilinoquinazoline compounds. The route involves the reaction of a6,7-disubstituted quinazolinone compound with a chlorinating agent and acatalyst in the absence of a solvent or with a chlorinating agent in thepresence of a trapping agent to provide a 6,7-disubstituted4-chloroquinazoline compound. The 6,7-disubstituted 4-chloroquinazolinecompound is then reacted with a substituted aniline compound, optionallyin the presence of a suitable base, to provide a hydrochloride salt ofthe 6,7-disubstituted 4-anilinoquinazoline compound, which may then beconverted to the free base. There is no disclosure in WO 98/10767 of7-benzyloxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline or of aprocess for its preparation.

The routes disclosed in the prior art documents for the preparation of acompound of the Formula VI are satisfactory for the synthesis ofrelatively small amounts of the compound. However, they all require theisolation and/or purification of intermediate compounds. This results ina satisfactory, but not high, overall yield of the compound of theFormula VI.

There is, therefore, a need for a more efficient synthesis of a compoundof the Formula VI suitable for use to make larger quantities of thatcompound. Preferably, the new synthesis should not involve costly andtime-consuming isolation and/or purification procedures. Thus, the newsynthesis should reduce the number of isolation and/or purificationprocedures required, thereby reducing costs and time of manufacture. Thenew synthesis should also allow for effective isolation of the compoundof the Formula VI in a crystalline form in high purity and yield, whichcrystalline form should have good filtration characteristics.

According to a second aspect of the present invention, there is provideda process for the manufacture of a compound of the Formula VI:

wherein R¹ is an acid labile protecting group;

-   from a compound of the Formula VII:

which process comprises the steps of:

-   (g) reacting the compound of the Formula VII with a suitable    chlorinating agent in the presence of a suitable base and a suitable    solvent, wherein the reaction is carried out by:    -   (g-1) adding a mixture of the compound of the Formula VII and        the base in the solvent to a mixture of the chlorinating agent        in the solvent at a temperature in the range of from 60 to 110°        C., conveniently 60 to 80° C. over a period of about 60 minutes;        or    -   (g-2) adding the chlorinating agent to a mixture of the compound        of the Formula VII and the base in the solvent at ambient        temperature over a period of about 15 minutes and then heating        the reaction mixture over a period of about 90 minutes to a        temperature in the range of from 70 to 90° C. and stirring the        reaction mixture at that temperature for about 1 hour; or    -   (g-3) adding the chlorinating agent to a mixture of the compound        of the Formula VII and the base in the solvent at a temperature        in the range of from 60 to 110° C., conveniently 70 to 90° C.        over a period of about 15 minutes,        to form a compound of the Formula VIII:

and

-   (h) reacting the compound of the Formula VIII with    4-bromo-2-fluoroaniline in situ in the presence of the solvent used    in step (g) to form a hydrochloride salt of the compound of the    Formula VI;

and whereafter the compound of the Formula VI obtained in the form ofthe hydrochloride salt may be converted into the free base or into theform of an alternative salt, if necessary.

The term ‘acid labile protecting group’ refers to groups which arereadily removed under acidic conditions. Suitable methods for protectionare those known to those skilled in the art. Conventional protectinggroups may be used in accordance with standard practice (forillustration see T. W. Green, Protective Groups in Organic Synthesis,John Wiley and Sons, 1991). Suitable protecting groups at R¹ includebenzyl, substituted benzyl (for example C₁₋₄alkoxybenzyl andC₁₋₄alkybenzyl), tert-butyl, 1,1-dimethyl-1-ethylmethyl, allyl,substituted allyl (such as C₁₋₄alkylallyl) or methoxyethoxymethyl. Inanother embodiment R¹ is benzyl.

The process of the second aspect of the invention is advantageous inthat it allows a compound of the Formula VI to be made in high purityand high yield on a larger scale. Typically, each of the steps of theprocess of the second aspect of the present invention proceeds ingreater than 90% yield.

A suitable solvent for step (g) is selected from an aryl alkyl ether,such as anisole, a dialkyl ether such as 1,2-dimethyl ether, a halosubstituted benzene such as chlorobenezene or trifluorotoluene or analkyl substituted benzene such as xylene, ethyl benzene or toluene. Inone embodiment of the invention the solvent for step (g) is anisole ortoluene. In another embodiment of the invention the solvent for step (g)is toluene.

Steps (g) and (h) are both conducted in the same solvent, which solventis selected from a suitable solvent as described above. This allows theprocess to be conducted as a continuous process without isolation and/orpurification of the intermediate compound of the Formula VIII. Thissignificantly reduces the time and cost of manufacturing the compound ofthe Formula VI on a larger scale. Additionally, the use of a singlesolvent may allow for solvent recycling, which increases the efficiencyof the process and provides environmental benefits. The use of tolueneor anisole as the reaction solvent is advantageous because thesesolvents minimise the formation of by-products that may be derived bydimerisation of the compound of the Formula VII, as discussed above. Thechoice of solvent also allows for the easy and convenient isolation ofthe compound of the Formula VI. For example, when the reaction mixtureis cooled to ambient temperature, the compound of the Formula VItypically forms a solid, which solid may then be collected by anyconventional method.

The mode of addition of the reagents in step (g) (i.e. as described insteps (g-1), (g-2) and (g-3)) is advantageous because it minimises theformation of by-products/impurities in that step. Typically, any suchby-products/impurities are predominantly formed by dimerisation of thecompound of the Formula VII. Reducing the formation ofby-products/impurities enables the intermediate compound of the FormulaVIII produced in step (g) to be used in step (h) without isolationand/or purification. Reducing the formation of by-products/impurities instep (g) also allows for the correct stoichiometry of the reagents instep (h) of the process and, therefore, a more efficient reaction inthat step. This is turn provides a high yield and high purity of thecompound of the Formula VI in step (h).

In one aspect of the invention, steps (g) and (h) are both conducted intoluene as the solvent. In another aspect of the invention, steps (g)and (h) are both conducted in anisole as the solvent. In yet anotheraspect of the invention, steps (g) and (h) are conducted in a solventmixture of toluene and anisole.

A suitable chlorinating agent for use in step (g) is phosphorusoxychloride. Typically, in step (g), a molar excess of chlorinatingagent is used relative to the compound of the Formula VII. For example,a molar excess in the range of from 1.3 to 2.0, conveniently in therange of from 1.7 to 1.8, may be used.

A suitable base for use in step (g) is a base selected fromtriethylamine and N,N-diisopropylethylamine. In particular, the base isN,N-diisopropylethylamine. The use of N,N-diisopropylethylamine as thebase in step (g) is advantageous because it minimises the formation ofby-products that may be derived by dimerisation of the compound of theFormula VII, as discussed above (for example as compared to the use oftriethylamine as the base in step (g)). Adding a source of chloride tothe reaction mixture (such as, for example, triethylamine hydrochloride)may also reduce the formation of such by-products.

In step (g-1), the reaction is carried out at a temperature in the rangeof from 60 to 110° C., conveniently 60 to 80° C., conveniently in therange of from 65 to 80° C., more conveniently in the range of from 70 to75° C.

In step (g-2), the addition of reagents is carried out at ambienttemperature. By the term “ambient temperature” we mean a temperature inthe range of from 10 to 30° C., especially a temperature in the range offrom 15 to 25° C., more especially a temperature of about 20° C. Thereaction mixture is then heated to a temperature in the range of from 70to 90° C., conveniently in the range of from 75 to 85° C., moreconveniently in the range of from 80 to 85° C.

In step (g-3), the reaction is carried out at a temperature in the rangeof from 60 to 110° C., conveniently 70 to 90° C., conveniently in therange of from 75 to 85° C., more conveniently in the range of from 80 to85° C.

In step (g), the term “of about” is used in the expressions “of about 60minutes”, “of about 15 minutes”, “of about 90 minutes and “of about 1hour” to indicate that the time periods quoted should not be construedas being absolute values because, as will be appreciated by thoseskilled in the art, the time periods may vary slightly. For example, thetime periods quoted may vary by ±50%, particularly by ±15%, particularlyby ±10% from the values quoted in step (g).

As the skilled person would appreciate, in step (g), the mixture of thecompound of the Formula VII and the base in a suitable solvent willtypically take the form of a suspension. The mixture of the chlorinatingagent in a solvent selected from toluene and anisole will typically takethe form of a solution. However, a number of factors may cause theseforms to vary. Such factors may, for example, include the amount of eachof the reagents added to the solvent, the particular base orchlorinating agent selected for use in step (g) and/or the temperatureselected for use in step (g).

The reaction of step (h) is carried out at a temperature in the range offrom 60 to 85° C., conveniently in the range of from 65 to 80° C., moreconveniently in the range of from 70 to 75° C.

In one aspect of the invention, following step (h) of the process, thecompound of the Formula VI is used directly in another process (forexample, in a process for manufacturing7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline as discussedbelow). In another aspect of the invention, following step (h) of theprocess, the compound of the Formula VI is isolated and/or purified, forexample before storage, handling and/or further reaction. Therefore, inone aspect of the invention, the process for manufacturing a compound ofthe Formula VI further includes the step (i) of isolating the compoundof the Formula VI. The step (i) may comprise any suitable steps orprocedures for isolating the desired product that are described in theliterature and/or that are known to the skilled person. Particular stepsthat would be of use would provide high quality and high purity product.The reaction mixture may be cooled to ambient temperature, at whichtemperature the compound of the Formula VI typically forms a solid, andthe solid so formed may be collected by any conventional method, forexample by filtration.

Both the compound of the Formula VII and the 4-bromo-2-fluoroanilinestarting material are commercially available or can be prepared usingconventional methods. For example the compound of Formula VII, whereinR¹ is benzyl, may be prepared as described in example 2 below,preparation of starting materials.

Another key intermediate that may be used in the preparation of ZD6474is 7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline, thecompound of the Formula IX:

Example 2 of WO 01/32651 and Example 24 of WO 97/32856 each disclose aroute for the preparation of a hydrochloride salt of a compound of theFormula IX. The route involves the reaction of a hydrochloride salt of7-benzyloxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline withtrifluoroacetic acid to provide the compound of the Formula IX.

As discussed above, WO 98/10767 discloses a route for the preparation of6,7-disubstituted 4-anilinoquinazoline compounds. There is no disclosurein WO 98/10767 of7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline or of aprocess for its preparation.

The routes disclosed in the prior art documents for the preparation of acompound of the Formula IX are satisfactory for the synthesis ofrelatively small amounts of the compound. However, they all require theisolation and/or purification of intermediate compounds. This results ina satisfactory, but not high, overall yield of the compound of theFormula IX.

There is, therefore, a need for a more efficient synthesis of thecompound of the Formula IX suitable for use to make larger quantities ofthat compound. Preferably, the new synthesis should not involve costlyand time-consuming purification procedures. Thus, the new synthesisshould reduce the number of isolation and/or purification proceduresrequired, thereby reducing costs and time of manufacture. Preferably,the new synthesis should minimise the number of solvents used throughoutthe process, which improves environmental performance and provides theopportunity for solvent recovery. The new synthesis should also enableeffective crystallisation of the compound of the Formula IX in acrystalline form with good filtration characteristics and in high purityand yield.

According to a third aspect of the present invention, there is provideda process for the manufacture of7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline, a compoundof the Formula IX:

from a compound of the Formula VII:

which process comprises the steps of:

-   (g) reacting the compound of the Formula VII with a suitable    chlorinating agent in the presence of a suitable base and a suitable    solvent, wherein the reaction is carried out by:    -   (g-1) adding a mixture of the compound of the Formula VII and        the base in the solvent to a mixture of the chlorinating agent        in the solvent at a temperature in the range of from 60 to 110°        C., conveniently 60 to 80° C. over a period of about 60 minutes;        or    -   (g-2) adding the chlorinating agent to a mixture of the compound        of the Formula VII and the base in the solvent at ambient        temperature over a period of about 15 minutes and then heating        the reaction mixture over a period of about 90 minutes to a        temperature in the range of from 70 to 90° C. and stirring the        reaction mixture at that temperature for about 1 hour; or    -   (g-3) adding the chlorinating agent to a mixture of the compound        of the Formula VII and the base in the solvent at a temperature        in the range of from 60 to 110° C., conveniently 70 to 90° C.        over a period of about 15 minutes,        to form a compound of the Formula VIII:

-   (h) reacting the compound of the Formula VIII with    4-bromo-2-fluoroaniline in situ in the presence of the solvent used    in step (g) to form a compound of the Formula VI;

and

-   (j) removing R¹ from the compound of the Formula VI in situ in the    presence of the solvent used in steps (g) and (h) to form the    compound of the Formula IX or a salt thereof;

and whereafter the compound of the Formula IX obtained in the form ofthe free base may be converted into a salt form and the compound of theFormula IX obtained in the form of a salt may be converted into the freebase or into the form of an alternative salt, if necessary.

The process of the third aspect of the invention is advantageous in thatit allows the compound of the Formula IX to be made in high purity andhigh yield on a larger scale. Typically, each of the steps of theprocess of the third aspect of the present invention proceeds in atleast 95% yield. Typically, the process of the third aspect of thepresent invention produces the compound of the Formula IX in at least85% yield.

Steps (g), (h) and (j) are all conducted in the same solvent, whichsolvent is selected from an aryl alkyl ether, such as anisole, a dialkylether such as 1,2-dimethyl ether, a halo substituted benzene such aschlorobenezene or trifluorotoluene or an alkyl substituted benzene suchas xylene, ethyl benzene or toluene. In one embodiment of the inventionthe solvent for step (g), (h) and (j) is anisole or toluene. In anotherembodiment of the invention the solvent for step (g), (h) and (j) istoluene. This allows the process to be conducted as a continuous processwithout isolation and/or purification of the intermediate compounds ofthe Formulae VIII and VI. This significantly reduces the time and costof manufacturing the compound of the Formula IX on a larger scale. Theuse of a single solvent may allow for solvent recycling, which increasesthe efficiency of the process and provides environmental benefits. Theuse of these solvents as the reaction solvent is advantageous becausethese solvents minimise the formation of by-products that may be derivedby dimerisation of the compound of the Formula VII, as discussed above.The choice of solvent also allows for the easy and convenient isolationof the compound of the Formula VI. For example, when the reactionmixture is cooled to ambient temperature, the compound of the Formula VItypically forms a solid, which may then be collected by any conventionalmethod.

As discussed above, the mode of addition of the reagents in step (g)(i.e. as described in steps (g-1), (g-2) and (g-3)) is advantageousbecause it minimises the formation of by-products/impurities in thatstep (which by-products/impurities typically are predominantly formed bydimerisation of the compound of the Formula VII). This enables theintermediate compound of the Formula VIII produced in step (g) to beused in step (h) without isolation and/or purification. Reducing theformation of by-products/impurities in step (g) allows for the correctstoichiometry of the reagents in step (h) of the process and, therefore,a more efficient reaction in that step. This is turn provides a highyield and high purity of the compound of the Formula VI in step (h).

In one aspect of the invention, steps (g), (h) and (j) are all conductedin toluene as the solvent. The use of toluene as the solvent in step (j)wherein R¹ is benzyl is advantageous because the toluene acts to capturethe benzyl cation that is generated during the deprotection reaction.This aids in the reducing the benzylated impurities that potentially maybe formed in step (j) of the process. Toluene also provides a morerobust crystallisation of compound IX and a crystalline form of compoundIX with superior filtration characteristics.

In another aspect of the invention, steps (g), (h) and (j) are allconducted in a single solvent such as anisole chlorobenezene,trifluorotoluene, xylene or ethyl benzene.

A suitable chlorinating agent for use in step (g) is phosphorusoxychloride. Typically, in step (g), a molar excess of chlorinatingagent is used relative to the compound of the Formula VII. For example,a molar excess in the range of from 1.3 to 2.0, conveniently in therange of from 1.7 to 1.8, may be used.

A suitable base for use in step (g) is a base selected fromtriethylamine, tripropylamine and N,N-diisopropylethylamine. Inparticular, the base is triethylamine. The use of triethylamine as thebase in step (g) is advantageous as it enables a more robustcrystallisation of compound IX and a crystalline form of compound IXwith superior filtration characteristics.

In step (g-1), the reaction is carried out at a temperature in the rangeof from 60 to 110° C., conveniently 60 to 80° C., conveniently in therange of from 65 to 75° C., more conveniently in the range of from 70 to75° C.

In step (g-2), the addition of reagents is carried out at ambienttemperature. By the term “ambient temperature” we mean a temperature inthe range of from 10 to 30° C., especially a temperature in the range offrom 15 to 25° C., more especially a temperature of about 20° C. Thereaction mixture is then heated to a temperature in the range of from 70to 90° C., conveniently in the range of from 75 to 85° C., moreconveniently in the range of from 80 to 85° C.

In step (g-3), the reaction is carried out at a temperature in the rangeof from 60 to 110° C., conveniently 70 to 90° C., conveniently in therange of from 75 to 85° C., more conveniently in the range of from 80 to85° C.

In step (g), the term “of about” is used in the expressions “of about 60minutes”, “of about 15 minutes”, “of about 90 minutes and “of about 1hour” to indicate that the time periods quoted should not be construedas being absolute values because, as will be appreciated by thoseskilled in the art, the time periods may vary slightly. For example, thetime periods quoted may vary by ±50%, particularly ±15%, particularly by±10% from the values quoted in step (g).

As the skilled person would appreciate, in step (g), the mixture of thecompound of the Formula VII and the base in a suitable solvent willtypically take the form of a suspension. The mixture of the chlorinatingagent in a solvent selected from toluene and anisole will typically takethe form of a solution. However, a number of factors may cause theseforms to vary. Such factors may, for example, include the amount of eachof the reagents added to the solvent and the particular base orchlorinating agent selected for use in step (g).

The reaction of step (h) is carried out at a temperature in the range offrom 60 to 90° C., conveniently 60 to 85° C., conveniently in the rangeof from 65 to 80° C., more conveniently in the range of from 70 to 75°C.

In this aspect of the invention, following the manufacture of thecompound of the Formula VI in step (h), the compound is used directly instep (j) for manufacturing a compound of the Formula IX. In other words,the compound of the Formula VI is not isolated as such but is used as asolution or slurry in a solvent selected from an aryl alkyl ether, suchas anisole, a dialkyl ether such as 1,2-dimethoxyethane, a halosubstituted benzene such as chlorobenezene or trifluorotoluene or analkyl substituted benzene such as xylene, ethyl benzene or toluene. Inone embodiment of the invention the solvent for step (j) is anisole ortoluene. In another embodiment of the invention the solvent for step (j)is toluene. Thereby, the compound of the Formula IX may be manufacturedfrom a compound of the Formula VII in a one-pot procedure.

A suitable method of removing the acid labile protecting group in situin step (j) is by reaction with an acid, such as trifluoroacetic acid.Optionally, a second acid (such as hydrogen chloride or hydrogenbromide) may be used in addition to, or as a replacement for, thetrifluoroacetic acid. When an acid is used to remove R¹ in step (j),then the compound of the Formula IX is obtained in the form of a salt.The use of trifluoroacetic acid in step (j) is advantageous because itallows for easy isolation of the compound of the Formula IX, for exampleby crystallisation from the trifluoroacetic acid by addition of waterand cooling or by addition of and aqueous alkali metal base such aspotassium hydroxide, sodium hydroxide, sodium acetate, potassiumacetate, more preferably potassium hydroxide followed by water andcooling. The crystalline solid so formed may be collected by anyconventional method, for example by filtration.

The reaction of step (j) is carried out at a temperature in the range offrom 60 to 90° C., conveniently 60 to 80° C., more conveniently in therange of from 70 to 75° C.

In one aspect of the invention, following step (j) of the process, thecompound of the Formula IX is isolated and/or purified. Any suitablesteps or procedures for isolating and/or purifying the desired productthat are described in the literature and/or that are known to theskilled person may be used. Particular steps that would be of use wouldprovide high quality and high purity product. For example, the compoundof the Formula IX may be isolated from trifluoroacetic acid by additionof water and cooling or more preferably by addition of and aqueousalkali metal base such as potassium hydroxide and water and cooling, asdiscussed above.

According to a fourth aspect of the present invention, there is provideda process for the manufacture of7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline, a compoundof the Formula IX:

from a compound of the Formula VII:

which process comprises the steps of:

-   (g) reacting the compound of the Formula VII with a suitable    chlorinating agent in the presence of a suitable base and a suitable    solvent selected from toluene and anisole, wherein the reaction is    carried out by:    -   (g-1) adding a mixture of the compound of the Formula VII and        the base in the solvent to a mixture of the chlorinating agent        in the solvent at a temperature in the range of from 60 to 110°        C., conveniently 60 to 80° C. over a period of about 60 minutes;        or    -   (g-2) adding the chlorinating agent to a mixture of the compound        of the Formula VII and the base in the solvent at ambient        temperature over a period of about 15 minutes and then heating        the reaction mixture over a period of about 90 minutes to a        temperature in the range of from 70 to 90° C. and stirring the        reaction mixture at that temperature for about 1 hour; or    -   (g-3) adding the chlorinating agent to a mixture of the compound        of the Formula VII and the base in the solvent at a temperature        in the range of from 60 to 110° C., conveniently 70 to 90° C.        over a period of about 15 minutes,        to form a compound of the Formula VIII:

-   (h) reacting the compound of the Formula VIII with    4-bromo-2-fluoroaniline in situ in the presence of the solvent used    in step (g) to form the compound of the Formula VI:

-   (i) isolating the compound of the Formula VI; and-   (k) removing R¹ from the compound of the Formula VI to form the    compound of the Formula IX or a salt thereof;

and whereafter the compound of the Formula IX obtained in the form ofthe free base may be converted into a salt form and the compound of theFormula IX obtained in the form of a salt may be converted into the freebase or into the form of an alternative salt such a trifluoroacetic acidor hydrochloride salt, if necessary.

The process of the fourth aspect of the invention is advantageous inthat it allows a compound of the Formula IX to be made in high purityand high yield on a larger scale.

Steps (g) and (h) are both conducted in the same solvent, which solventis selected from an aryl alkyl ether, such as anisole, a dialkyl ethersuch as 1,2-dimethyl ether, a halo substituted benzene such aschlorobenezene or trifluorotoluene or an alkyl substituted benzene suchas xylene, ethyl benzene or toluene. In one embodiment of the inventionthe solvent for step (g) and (h) is anisole or toluene. In anotherembodiment of the invention the solvent for step (g) and (h) is toluene.This allows the process to be conducted as a continuous process withoutisolation and/or purification of the intermediate compound of theFormula VIII. This significantly reduces the time and cost ofmanufacturing the compound of the Formula IX on a larger scale. The useof a single solvent in steps (g) and (h) may allow for solventrecycling, which increases the efficiency of the process and providesenvironmental benefits. The use of toluene or anisole as the reactionsolvent in steps (g) and (h) is advantageous because these solventsminimise the formation of by-products that may be derived bydimerisation of the compound of the Formula VII, as discussed above. Thechoice of solvent also allows for the easy and convenient isolation ofthe compound of the Formula VI. For example, when the reaction mixtureis cooled to ambient temperature, the compound of the Formula VItypically forms a solid, which solid may then be collected by anyconventional method.

As discussed above, the mode of addition of the reagents in step (g)(i.e. as described in steps (g-1), (g-2) and (g-3)) is advantageousbecause it minimises the formation of by-products/impurities in thatstep (which by-products/impurities typically are predominantly formed bydimerisation of the compound of the Formula VII). This enables theintermediate compound of the Formula VIII produced in step (g) to beused in step (h) without isolation and/or purification. Reducing theformation of by-products/impurities in step (g) allows for the correctstoichiometry of the reagents in step (h) of the process and, therefore,a more efficient reaction in that step. This is turn provides a highyield and purity of the compound of the Formula VI in step (h).

In one aspect of the invention, steps (g) and (h) are both conducted intoluene as the solvent. In another aspect of the invention, steps (g)and (h) are both conducted in anisole as the solvent.

A suitable chlorinating agent for use in step (g) is phosphorusoxychloride. Typically, in step (g), a molar excess of chlorinatingagent is used relative to the compound of the Formula VII. For example,a molar excess in the range of from 1.3 to 2.0, conveniently in therange of from 1.7 to 1.8, may be used.

A suitable base for use in step (g) is a base selected fromtriethylamine and N,N-diisopropylethylamine. In one embodiment, the baseis triethylamine. The use of triethylamine as the base in step (g) isadvantageous as it enables a more robust crystallisation of compound IXand a crystalline form of compound IX with superior filtrationcharacteristics.

In another embodiment, the base is N,N-diisopropylethylamine. The use ofN,N-diisopropylethylamine as the base in step (g) is advantageousbecause it minimises the formation of by-products that may be derived bydimerisation of the compound of the Formula VII, as discussed above (forexample as compared to the use of triethylamine as the base in step(g)). Adding a source of chloride to the reaction mixture (such as, forexample, triethylamine hydrochloride) may also reduce the formation ofsuch by-products.

In step (g-1), the reaction is carried out at a temperature in the rangeof from 60 to 110° C., conveniently 60 to 80° C., conveniently in therange of from 65 to 75° C., more conveniently in the range of from 70 to75° C.

In step (g-2), the addition of reagents is carried out at ambienttemperature. By the term “ambient temperature” we mean a temperature inthe range of from 10 to 30° C., especially a temperature in the range offrom 15 to 25° C., more especially a temperature of about 20° C. Thereaction mixture is then heated to a temperature in the range of from 70to 90° C., conveniently in the range of from 75 to 85° C., moreconveniently in the range of from 80 to 85° C.

In step (g-3), the reaction is carried out at a temperature in the rangeof from 60 to 110° C., conveniently 70 to 90° C., conveniently in therange of from 75 to 85° C., more conveniently in the range of from 80 to85° C.

In step (g), the term “of about” is used in the expressions “of about 60minutes”, “of about 15 minutes”, “of about 90 minutes and “of about 1hour” to indicate that the time periods quoted should not be construedas being absolute values because, as will be appreciated by thoseskilled in the art, the time periods may vary slightly. For example, thetime periods quoted may vary by ±50%, particularly ±15%, particularly by±10% from the values quoted in step (g).

As the skilled person would appreciate, in step (g), the mixture of thecompound of the Formula VII and the base in a suitable solvent willtypically take the form of a suspension. The mixture of the chlorinatingagent in a solvent selected from toluene and anisole will typically takethe form of a solution. However, a number of factors may cause theseforms to vary. Such factors may, for example, include the amount of eachof the reagents added to the solvent and the particular base orchlorinating agent selected for use in step (g).

The reaction of step (h) is carried out at a temperature in the range offrom 60 to 90° C., conveniently 60 to 90° C., conveniently in the rangeof from 65 to 80° C., more conveniently in the range of from 70 to 75°C.

In this aspect of the invention, following the manufacture of thecompound of the Formula VI in step (h), the compound is isolated and,optionally, purified in step (i) of the process. The isolated compoundof the Formula VI is then used in step (k) for manufacturing a compoundof the Formula IX, either immediately or following storage for anappropriate period of time. The isolation of the compound of the FormulaVI in step (i) wherein R¹ is benzyl is advantageous because it enables abroader choice of methods for removing the benzyl group from thecompound of the Formula VI in step (k), for example compared to whenthis step is conducted in situ.

The step (k) wherein R¹ is benzyl may comprise any suitable steps orprocedures for removing the benzyl group that are described in theliterature and/or that are known to the skilled person. Particular stepsthat would be of use would provide high quality and high purity product.For example, in step (k) the benzyl group may be removed by reactionwith a suitable hydrogenation agent, such as palladium on carbon, forexample in the presence of a suitable moderating agent, such as zincbromide or zinc iodide. The use of a hydrogenation agent is advantageousbecause it provides a highly efficient method of removing the benzylgroup in step (k) and because it allows for the efficient removal ofby-products from the waste stream.

A further suitable method of removing the acid labile protecting groupwherein R¹ is a benzyl group in step (k) is by reaction with an acid,such as trifluoro acetic acid. Optionally, a second acid (such ashydrogen chloride or hydrogen bromide) may be used in addition to, or asa replacement for, the trifluoroacetic acid. When an acid is used toremove the benzyl group in step (k), then the compound of the Formula IXis obtained in the form of a salt. The use of trifluoroacetic acid instep (k) is advantageous because it allows for easy isolation of thecompound of the Formula IX, for example by crystallisation from thetrifluoroacetic acid by addition of water and cooling or more preferablyby addition of an aqueous alkali metal base such as potassium hydroxide,sodium hydroxide, sodium acetate, potassium acetate, more preferablypotassium hydroxide followed by water and cooling. The crystalline solidso formed may be collected by any conventional method, for example byfiltration.

The reaction of step (k) wherein R¹ is benzyl may be carried out at anytemperature and in any solvent suitable for the particular method ofremoval of the benzyl group being used. Examples of suitable solventsfore acid-based removal of the benzyl group include ethanol, an arylalkyl ether, such as anisole, a dialkyl ether such as 1,2-dimethylether, a halo substituted benzene such as chlorobenezene ortrifluorotoluene or an alkyl substituted benzene such as xylene, ethylbenzene or toluene or dichloromethane.

In one aspect of the invention, following step (k) of the process, thecompound of the Formula IX is isolated and/or purified. Any suitablesteps or procedures for isolating and/or purifying the desired productthat are described in the literature and/or that are known to theskilled person may be used. Particular steps that would be of use wouldprovide high quality and high purity product.

Another key intermediate that may be used in the preparation of ZD6474is7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline,the compound of the Formula X:

Example 2 of WO 01/32651 discloses a route for the preparation of acompound of the Formula X. The route involves the reaction of7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline withpotassium carbonate and1-(tert-butoxycarbonyl)-4-(4-methylphenylsulfonyloxymethyl)piperidine ina N,N-dimethylformamide solvent to provide the compound of the FormulaX.

As discussed above, WO 98/10767 discloses a route for the preparation of6,7-disubstituted 4-anilinoquinazoline compounds. There is no disclosurein WO 98/10767 of7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazolineor of a process for its preparation.

The routes disclosed in the prior art documents for the preparation of acompound of the Formula X are satisfactory for the synthesis ofrelatively small amounts of the compound. However, there is a need for amore efficient synthesis of the compound of the Formula X suitable foruse to make larger quantities of that compound. Preferably, the newsynthesis should not involve costly and time-consuming purificationprocedures. Thus, the new synthesis should reduce the number ofisolation and/or purification procedures required, thereby reducingcosts and time of manufacture. Preferably, the new synthesis shouldminimise the number of solvents used throughout the process, whichimproves environmental performance and provides the opportunity forsolvent recovery. The new synthesis should also provide the compound ofthe Formula X in a high purity and in a high yield.

According to a fifth aspect of the present invention, there is provideda process for the manufacture of7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline,a compound of the Formula X:

from a compound of the Formula VII:

which process comprises the steps of converting the compound of theFormula VII to a compound of the Formula IX:

by conducting a process as discussed above in relation to the third orthe fourth aspect of the invention; and

-   (l) reacting the compound of the Formula IX with a compound of the    Formula II as defined above in the presence of a suitable base to    provide a compound of the Formula X or a salt thereof;

and whereafter the compound of the Formula X obtained in the form of thefree base in either solvated or non-solvated forms may be converted intoa salt form and the compound of the Formula X obtained in the form of asalt may be converted into the free base or into the form of analternative salt, if necessary.

The process of the fifth aspect of the invention is advantageous in thatit allows the compound of the Formula X to be made in high purity andhigh yield on a larger scale. Typically the process of the fifth aspectof the present invention proceeds in greater than 80% yield. The processof the fifth aspect of the invention is also advantageous for at leastthe reasons discussed above in relation to the third and fourth aspectsof the invention.

Typically, the compound of the Formula IX is isolated and/or purifiedbefore step (l) is conducted, for example using any suitable steps orprocedures that are described in the literature and/or that are known tothe skilled person as discussed above.

In another embodiment of the invention following the manufacture of thecompound of the Formula IX in step (j) wherein R¹ is benzyl (orsubstituted benzyl) and when hydrogenation is used as the method ofdeprotection of the benzyl group, the compound is used directly in step(l) for manufacturing a compound of the Formula X. In other words, thecompound of the Formula IX is not isolated as such but is used as asolution or slurry in a suitable solvent such as N-methyl pyrrolidone,dimethylformamide or dimethylacetamide. In one embodiment of theinvention the solvent for step (j) is N-methylpyrolidone. Thereby, thecompound of the Formula X may be manufactured from a compound of theFormula VIII in a one-pot procedure.

A suitable base for use in step (l) is selected from sodium carbonate,sodium bicarbonate, potassium carbonate, sodium hydroxide, potassiumtert-butanol, and potassium hydroxide.

Step (l) may be conducted in any suitable solvent and at any suitabletemperature.

When the base used in step (l) is selected from sodium carbonate andpotassium carbonate, suitable solvents include, for example,N-methylpyrrolidone, N-ethylpyrrolidone, dimetylacetamide,dimethylsulphoxide, sulpholine, methylethyl ketone andN,N-dimethylformamide. In this aspect, step (l) typically may beconducted at a temperature in the range of from 60 to 120° C.,conveniently 70 to 105° C., conveniently in the range of from 80 to 100°C., conveniently in the range 70-90° C., conveniently in the range offrom 90 to 95° C. In a further embodiment in the range 75-85° C.

When the base used in step (l) is selected from sodium hydroxide andpotassium hydroxide, suitable solvents include, for example, an arylalkyl ether, such as anisole, a dialkyl ether such as1,2-dimethoxyethane, a halo substituted benzene such as chlorobenezeneor trifluorotoluene or an alkyl substituted benzene such as xylene,ethyl benzene or toluene or acetonitrile. In one embodiment of theinvention the solvent for step (l) is anisole or toluene. In anotherembodiment of the invention the solvent for step (l) is toluene. In thisaspect, step (l) typically may be conducted at a temperature in therange of from 60 to 90° C., conveniently in the range of from 65 to 85°C., conveniently in the range of from 70 to 80° C. In this aspect, step(l) may conveniently be conducted by adding water, the base (such assodium hydroxide or potassium hydroxide) and a suitable phase transfercatalyst in toluene to the reaction mixture. Suitable phase transfercatalysts include, for example, tetrabutylammonium bromide and Adogen®464 (methyltrialkyl(C₈₋₁₀) ammonium chloride, CAS 63393-96-4).

In one aspect, the process of the fifth aspect of the invention mayinclude the step (m) of isolating the compound of the Formula X. Thestep (m) may comprise any suitable steps or procedures for isolating thecompound of the Formula X that are described in the literature and/orthat are known to the skilled person.

For example, when the base used in step (l) is selected from sodiumcarbonate and potassium carbonate, step (m) may comprise the steps of:

-   -   (m-1) adding water and allowing crystallisation of the compound        of the Formula X to occur, collecting the compound of the        Formula X and washing the compound of the Formula X with water,        followed by a solvent selected from ethyl acetate, butyl acetate        and acetonitrile at a temperature in the range of from 25 to 55°        C., conveniently from 45 to 55° C.; or    -   (m-2) adding water and an alcohol selected from methanol,        ethanol, isopropanol and n-propanol (particularly isopropanol)        and allowing crystallisation of the compound of the Formula X to        occur, collecting the compound of the Formula X and washing the        compound of the Formula X with a mixture of water and the        alcohol selected from selected from methanol, ethanol,        isopropanol and n-propanol, followed by a solvent selected from        ethyl acetate, butyl acetate and acetonitrile at a temperature        in the range of from 25 to 55° C., conveniently from 45 to 55°        C.

The steps (m-1) and (m-2) are advantageous because they are efficient atremoving unreacted compound of the Formula IX, as well as impuritiesthat are routinely formed during step (l) of the process. Suchimpurities include those formed by reaction of the compound of theFormula II at the 1-position nitrogen atom in the quinazoline ringinstead of at the desired position at the hydroxy substituent.

When the base used in step (l) is selected from sodium hydroxide andpotassium hydroxide, step (m) may comprise the steps of allowingcrystallisation of the compound of the Formula X to occur (for exampleto crystallise from the toluene phase) and collecting the compound ofthe Formula X by any conventional method. This aspect is advantageousbecause the compound of the Formula X crystallises directly from thereaction mixture in high yield (for example at least 80% yield) and inhigh quality without the need to further purify the product.

In steps (m), the compound of the Formula X so formed (for example whichis isolated as a crystalline solid) may be collected by any conventionalmethod, for example by filtration. The collected crystalline solid may,if necessary, then be washed with the appropriate solvent and may thenbe dried.

According to a sixth aspect of the present invention, there is provideda process for the manufacture of7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline,a compound of the Formula X:

from 7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline, acompound of the Formula IX:

-   (l) reacting the compound of the Formula IX with a compound of the    Formula II as defined above in the presence of a suitable base to    provide a compound of the Formula X or a salt thereof; and-   (m) isolating the compound of the Formula X by:    -   (m-1) adding water and allowing crystallisation of the compound        of the Formula X to occur, collecting the compound of the        Formula X and washing the compound of the Formula X with water,        followed by a solvent selected from ethyl acetate, butyl acetate        and acetonitrile at a temperature in the range of from 25 to 55°        C., conveniently 45 to 55° C.; or    -   (m-2) adding water and an alcohol selected from methanol,        ethanol, isopropanol and n-propanol (particularly isopropanol)        and allowing crystallisation of the compound of the Formula X to        occur, collecting the compound of the Formula X and washing the        compound of the Formula X with a mixture of water and the        alcohol selected from methanol, ethanol, isopropanol and        n-propanol, followed by a solvent selected from ethyl acetate,        butyl acetate and acetonitrile at a temperature in the range of        from 25 to 55° C., conveniently 25 to 55° C.;

and whereafter the compound of the Formula X obtained in the form of thefree base in either solvated or non solvated forms (or solvate ofsolvents from NMP, Ethyl Acetate or a mixture of both) may be convertedinto a salt form and the compound of the Formula X obtained in the formof a salt may be converted into the free base or into the form of analternative salt, if necessary.

The process of the sixth aspect of the invention is advantageous in thatit allows the compound of the Formula X to be made in high purity andhigh yield on a larger scale. Typically, each of the steps of theprocess of the sixth aspect of the present invention proceeds in greaterthan 80% yield.

The process provides for the efficient removal of any unreacted compoundof the Formula IX, as well as of any impurities that are routinelyformed during step (l) of the process. Such impurities include thoseformed by reaction of the compound of the Formula II at the 1-positionnitrogen atom in the quinazoline ring instead of at the desired positionat the hydroxy substituent.

A suitable base for use in step (l) is selected from sodium carbonate,sodium hydroxide, potassium hydroxide and potassium carbonate.

Step (l) may be conducted in any suitable solvent or at any suitabletemperature.

When the base used in step (l) is selected from sodium carbonate andpotassium carbonate, suitable solvents include, for example,N-methylpyrrolidone, N-ethylpyrrolidone and N,N-dimethylformamide. Inthis aspect, step (l) typically may be conducted at a temperature in therange of from 70 to 105° C., conveniently of from 80 to 100° C.,conveniently of from 90 to 95° C.

The steps (m-1) and (m-2) are advantageous because they are efficient atremoving unreacted compound of the Formula IX, as well as impuritiesthat are routinely formed during step (l) of the process. Suchimpurities include those formed by reaction of the compound of theFormula II at the 1-position nitrogen atom in the quinazoline ringinstead of at the desired position at the hydroxy substituent.

In steps (m-1) and (m-2), the crystalline solid so formed may becollected by any conventional method, for example by filtration. Thecollected crystalline solid may, if necessary, then be washed with theappropriate solvent and may then be dried.

The compound of the Formula II used in step (l) of the processes of thefifth and sixth aspects of the invention may be obtained by anyliterature or conventional method. In one aspect of the invention, thecompound of the Formula II used in step (l) of the fifth or sixth aspectof the invention is prepared according to the process of the firstaspect of the invention, as discussed above.

According to a seventh aspect of the invention, there is provided aprocess for the manufacture of ZD6474:

from a compound of the Formula X:

which process comprises the steps of:

-   (n) reacting the compound of the Formula X with formic acid and    formaldehyde or a polymer of formaldehyde, conveniently in water at    a temperature in the range of from 70 to 95° C., conveniently 70 to    90° C. to form a formic acid salt of ZD6474;-   (o) adding an inert organic solvent selected from tetrahydrofuran,    butyronitrile and methanol and a suitable base so as to form the    free base of ZD6474;

whereafter the ZD6474 obtained in the form of the free base may beconverted into a pharmaceutically acceptable salt, if necessary.

In step (n) of the process of the seventh aspect of the invention, thereaction proceeds via a transient intermediate, which intermediate is4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline,a compound of the Formula XI:

The process of the seventh aspect of the invention is advantageous inthat it allows the ZD6474 to be made in high purity and high yield on alarger scale. Typically, each of the steps of the process of the seventhaspect of the present invention proceeds in greater than 90% yield.

The compound of the Formula X used in step (n) of the process of theseventh aspect of the invention may be obtained by any literature orconventional method (for example, as described in WO 01/32651 discussedpreviously). Alternatively, in one aspect of the invention, the compoundof the Formula X used in step (n) of the seventh aspect of the inventionis prepared according to the process of the fifth or the sixth aspect ofthe invention, as discussed above.

Step (n) is conducted at a temperature in the range of from 70 to 95°C., conveniently 70 to 90° C., conveniently in the range of from 75 to85° C., more conveniently at about 80° C.

Preferably, step (n) is conducted under an inert atmosphere, for exampleunder a nitrogen atmosphere. This is advantageous because the process ofstep (n) may produce hydrogen gas and carbon monoxide as a by-product,which hydrogen gas must be removed from the reaction vessel in a safeand effective manner

In step (n), the formic acid salt of ZD6474 is produced. This salt isconverted to the free base of ZD6474 in step (o) of the process.

In step (n) examples of polymers of formaldehyde includeparaformaldehyde and s-trioxane (1,3,5 trioxane).

A suitable inert organic solvent for use in step (o) is selected fromtetrahydrofuran, butyronitrile and methanol (particularlytetrahydrofuran or methanol). The inert organic solvent is added to thereaction mixture after the completion of the reaction in step (n). Asthe skilled person would appreciate, it may be necessary to cool thereaction mixture before the inert organic solvent is added.

A suitable base for use in step (o) is sodium hydroxide or potassiumhydroxide (particularly potassium hydroxide). The addition of a base instep (o) converts the formic acid salt of ZD6474 to the free base ofZD6474.

When the inert organic solvent used in step (o) is selected fromtetrahydrofuran and butyronitrile, the ZD6474 product is effectivelytransferred from the aqueous phase to the organic phase. This isbecause, once made, the free base of ZD6474 is preferentially soluble inthe inert organic solvent (whereas the formic acid salt of ZD6474 issoluble in the aqueous phase). When the inert organic solvent used instep (o) is methanol, the free base of ZD6474 typically crystallisesdirectly from the reaction mixture. When the base is potassium hydroxidethis is particularly advantageous as the formate salt are completelysoluble in the methanol solvent and don't contaminate the isolatedcompound ZD6474. This also provide a crystalline compound with goodfiltration characteristics. (this can be isolated as either theanhydrate form, a methanoate form or a mixed methanoate hydrate). Thus,step (o) of the process is advantageous because it aids and simplifiesthe isolation and purification of the ZD6474 product, particularly whenthe process is conducted on a larger scale.

Step (o) is conducted at a temperature in the range of from 30 to 70°C., conveniently in the range of from 40 to 65° C., more conveniently inthe range of from 40 to 60° C.

In one aspect, the process of the seventh aspect of the invention mayinclude the step (p) of isolating and/or purifying the free base of theZD6474. The step (p) may comprise any suitable steps or procedures forisolating and/or purifying the free base of ZD6474 that are described inthe literature and/or that are known to the skilled person.Alternatively, for example, when the inert organic solvent used in step(o) is selected from tetrahydrofuran and butyronitrile, the step (p) maycomprise the steps of:

-   -   (p-1) separating and removing the aqueous phase from the organic        phase;    -   (p-2) charging n-butyl acetate to the organic phase;    -   (p-3) washing the organic phase with water and separating and        removing the aqueous phase from the organic phase;    -   (p-4) adding tetrahydrofuran and n-butyl acetate to the organic        phase;    -   (p-5) distilling the organic phase so as to substantially remove        the water and the tetrahydrofuran and to provide a suspension of        ZD6474 in predominately n-butyl acetate;    -   (p-6) allowing crystallisation of the ZD6474 to complete; and    -   (p-7) collecting the ZD6474.

The steps (p-1), (p-2) and (p-3) are advantageous because they readilyand easily remove formic acid salts and residual formaldehyde or polymerof formaldehyde from the ZD6474 product dissolved in the organic phase.

In one aspect, the steps (p-1), (p-2), (p-3) and (p-4) are eachconducted at a temperature in the range of from 50 to 65° C.,conveniently in the range of from 55 to 65° C., more conveniently ofabout 60° C.

Typically, steps (p-1), (p-2) and (p-3) may each be repeated twicebefore step (p-4) is conducted.

Step (p-5) substantially removes any water and tetrahydrofuran that ispresent in the organic phase that has been separated from the aqueousphase in steps (p-1) and (p-3). The distillation is conducted so as toprovide a solvent composition that contains about 90% w/w n-butylacetate. In other words, the solution of ZD6474 in predominantly n-butylacetate is a solution of ZD6474 in a solvent composition that containsabout 90% w/w n-butyl acetate. Typically, the distillation is conducteduntil an internal temperature in the range of from 90 to 110° C.,conveniently 90 to 104° C. is achieved conveniently in the range of from100-110° C. The distillation in step (p-5) is conveniently conducted atatmospheric pressure (or reduced pressure but more conveniently atambient pressure).

For the avoidance of doubt in (p-6) where it refers to ‘allowingcrystallisation of the ZD6474 to complete’ this means that thecrystallisation process has completed at the conditions used, it doesnot mean that 100% of the ZD6474 in the reaction mixture hascrystallised.

An alternative step (p) of isolating and/or purifying the free base ofZD6474, when the inert organic solvent used in step (o) istetrahydrofuran, may comprise the steps of:

(p-8) adding water to the ZD6474 solution in the organic phase obtainedafter step (p-1) so as to allow crystallisation of the ZD6474 to occur;and

(p-9) collecting the ZD6474.

In each of the above isolation steps, the crystalline solid so formedmay be collected by any conventional method, for example by filtration.The collected crystalline solid may, if necessary, then be purifiedfurther, and may then be dried.

The step (p) of isolating the ZD6474 product is advantageous because itprovides ZD6474 in a high yield (for example typically in greater than90% yield) and a high purity (for example typically in greater than 99%purity). In addition, the step (p) provides a form of ZD6474 that iseasily filterable on a larger scale.

In another aspect of the present invention, the ZD6474 preparedaccording to the process of the seventh aspect of the invention asdiscussed above may be further purified. The further purification ofZD6474 may comprise any suitable steps or procedures for isolatingand/or purifying ZD6474 that are described in the literature and/or thatare known to the skilled person. Alternatively, the further purificationof the ZD6474 may comprise the steps of heating a suspension of theZD6474 as prepared in the process of the seventh aspect of the presentinvention in a mixture of tetrahydrofuran, water and butyl acetate toreflux, cooling the resulting mixture to a temperature in the range offrom 50 to 65° C. (conveniently of about 60° C.), separating the aqueousand organic phases and filtering the organic phase. The filtrate maythen be combined with further tetrahydrofuran and butyl acetate and theresulting mixture heated to a temperature in the range of 90 to 110° C.,conveniently 90 to 110° C. (conveniently in a range of from 100 to 110°C.) before being cooled to a temperature in the range of from 40 to −10°C., conveniently 25 to 0° C. (conveniently in the range of from 0 to 10°C., more conveniently of about 5° C., in a further embodiment at atemperature of about 25° C.) to provide a slurry of ZD6474. The ZD6474may then be collected by any conventional method, for example byfiltration, and optionally washed with ethyl acetate. This isadvantageous because the described process reduces the level of water atthe end of the distillation to below 1% thus ensuring that theanhydrrous form of ZD6474 is produced.

Alternatively, for example, when the inert organic solvent used in step(o) is tetrahydrofuran, the step (p) may comprise the steps of:

-   -   (p-1) separating and removing the aqueous phase from the organic        phase;    -   (p-2) filtering the organic phase;    -   (p-3) charging n-butyl acetate to the organic phase;    -   (p-4) washing the organic phase with water and separating and        removing the aqueous phase from the organic phase;    -   (p-5) adding tetrahydrofuran and n-butyl acetate to the organic        phase;    -   (p-6) distilling the organic phase so as to substantially remove        the water and the tetrahydrofuran and to provide a suspension of        ZD6474 in predominately n-butyl acetate;    -   (p-7) cooling and charging additional tetrahydrofuran; and    -   (p-8) allowing crystallisation of the ZD6474 to complete; and    -   (p-9) collecting the ZD6474.

The step (p-7) is advantageous because it improves the quality of theproduct obtained by solubilising the impurities in the mother liquors.This allows the telescoping of the production of the Crude API (ActivePharmaceutical Ingredient) with the isolation of the purified API in asingle step.

According to an eighth aspect of the present invention, there isprovided a process for the manufacture of ZD6474 from a compound of theFormula VII:

which process comprises the steps of:

-   (g) reacting the compound of the Formula VII with a suitable    chlorinating agent in the presence of a suitable base and a solvent    selected from chlorobenezene, trifluorotoluene, xylene, ethyl    benzene, toluene & anisole more specifically anisole and toluene,    wherein the reaction is carried out by:    -   (g-1) adding a mixture of the compound of the Formula VII and        the base in the solvent to a mixture of the chlorinating agent        in the solvent at a temperature in the range of from 60 to 90°        C., conveniently 60 to 80° C. over a period of about 60 minutes;        or    -   (g-2) adding the chlorinating agent to a mixture of the compound        of the Formula VII and the base in the solvent at ambient        temperature over a period of about 15 minutes and then heating        the reaction mixture over a period of about 90 minutes to a        temperature in the range of from 70 to 90° C. and stirring the        reaction mixture at that temperature for about 1 hour; or    -   (g-3) adding the chlorinating agent to a mixture of the compound        of the Formula VII and the base in the solvent at a temperature        in the range of from 60 to 110° C., conveniently 70 to 90° C.        over a period of about 15 minutes,        to form a compound of the Formula VIII:

-   (h) reacting the compound of the Formula VIII with    4-bromo-2-fluoroaniline in situ in the presence of the solvent used    in step (g) to form a compound of the Formula VI:

-   (j) removing R¹ from the compound of the Formula VI in situ in the    presence of the solvent used in steps (g) and (h) to form the    compound of the Formula IX:

-   (l) reacting the compound of the Formula IX with a compound of the    Formula II as defined above in the presence of a suitable base to    provide a compound of the Formula X;

-   (n) reacting the compound of the Formula X with formic acid and    formaldehyde or a polymer of formaldehyde conveniently in water at a    temperature in the range of from 70 to 90° C. to form the formic    acid salt of ZD6474; and-   (o) adding an inert organic solvent selected from tetrahydrofuran,    butyronitrile and methanol and a suitable base so as to form the    free base of ZD6474; and optionally-   (p) further purifying ZD6474 in a mixture of tetrahydrofuran, water    and butyl acetate to provide a required crystalline anhydrous form    suitable for tablet manufacture.

whereafter the ZD6474 obtained in the form of the free base may beconverted into a pharmaceutically acceptable salt form, if necessary.

The process of the eighth aspect of the invention is advantageous inthat it allows the ZD6474 to be made in high purity and high yield on alarger scale. Typically, each of the steps of the process of the seventhaspect of the present invention proceeds in greater than 90% yield.

Preferred aspects of the process of the eighth aspect of the inventionare as set out above in relation to individual steps as described in thefirst, second, third, fourth, fifth, sixth and seventh aspects of thepresent invention. In particular, preferred aspects of the process ofthe eighth aspect of the invention are as set out above, for example, inrelation to individual steps of the third, fifth, sixth and/or seventhaspects of the present invention.

Conveniently, steps (g), (h) and (j) of the process of the eighth aspectof the present invention are all conducted in toluene as the solvent andtriethylamine as the base.

Conveniently, a suitable method of removing the benzyl group in situ instep (j) of the process of the eighth aspect of the present invention,wherein R¹ is benzyl, is by reaction with trifluoroacetic acid.

Conveniently, the base used in step (l) of the process of the eighthaspect of the present invention is potassium carbonate and the suitablesolvent is N-methylpyrrolidone.

The process of the eighth aspect of the present invention typically mayinclude the step (m) of isolating the compound of the Formula X beforesteps (n) and (o) are conducted. Conveniently, the step (m) may beconducted as hereinbefore described.

Conveniently, a suitable base for use in step (o) of the eighth aspectof the present invention is potassium hydroxide.

Conveniently, a suitable solvent for use in step (o) of the eighthaspect of the present invention is methanol.

The process of the eighth aspect of the present invention may includethe step (p) of isolating and/or purifying the free base of the ZD6474.The step (p) may be conducted as hereinbefore described.

The invention is illustrated hereinafter by means of the followingnon-limiting Examples and Data in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

(ii) yields are given for illustration only and are not necessarily themaximum attainable;

(iii) melting points are uncorrected and were determined using a MettlerDSC820e;

(iv) the structures of the end-products were confirmed by nuclear(generally proton) magnetic resonance (NMR) and mass spectraltechniques; proton magnetic resonance chemical shift values weremeasured on the delta scale and peak multiplicities are shown asfollows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q,quartet, quin, quintet; all samples run on a Bruker DPX 400 MHz at 300Kin the solvent indicated, 16 scans, pulse repetition time 10 seconds;

(v) intermediates were not generally fully characterised and purity wasassessed by NMR analysis;

(vi) chemical symbols have their usual meanings; SI units and symbolsare used; and

(vii) the following abbreviations have been used:

-   -   THF tetrahydrofuran    -   IPA isopropanol    -   DMSO dimethylsulfoxide    -   TEDA triethylenediamine    -   DIPEA N,N-diisopropylethylamine    -   TFA trifluoroacetic acid    -   NMP N-methylpyrrolidinone    -   DMF N,N-dimethylformamide    -   DMA N,N-dimethylacetamide    -   v/v volume/volume ratio    -   w/w weight/weight ratio    -   w/v weight/volume ratio

EXAMPLE 1 Preparation of1-(tert-butoxycarbonyl)-4-(4-methylphenylsulfonyloxymethyl)-piperidine(the compound of the Formula II)

Di-tert-butyl dicarbonate (88.63 g) in toluene (296 ml) was added to astirred solution of ethyl isonipecotate (62.88 g) in toluene (317 ml).The reaction mixture was then distilled at atmospheric pressure,removing about 130 ml of distillate, with a final distillationtemperature of 112° C. Sodium bis(2-methoxyethoxy)aluminium hydride(Red-A1, 65% w/w solution in toluene, 161 g) in toluene (220 ml) wasthen added to the reaction mixture over a period of about 60 minutes. Asolution of 0.5 molar Rochelle Salt (191 ml) was added to the reactionmixture and the aqueous phase was separated at 40° C. The organic phasewas washed with 15% w/v brine (3×136 ml) and with water (136 ml). Thesolution was distilled at atmospheric temperature, removing about 400 mlof distillate, with a final distillation temperature of 112° C.Triethylenediamine (51.62 g) was added to the reaction mixture followedby tosyl chloride (87.90 g) in toluene (416 ml) over a period of about60 minutes. Sodium hydroxide (2N, 160 ml) was added to the reactionmixture and the organic layer separated and washed successively withwater (80 ml), citric acid (0.5M, 80 ml) and water (80 ml). The organicphase was concentrated at reduced pressure with a maximum internaltemperature of 70° C., collecting about 600 ml of distillate. Thesolution was cooled to 20° C. and isohexane (160 ml) was added. Oncecrystallisation had occurred, further isohexane (320 ml) was added. Theproduct was temperature cycled to 40° C., the suspension was cooled to5° C. and the product was isolated by filtration and dried at 40° C.Yield: 127.9 g, 86.5%; NMR Spectrum (CDCl₃) 1.0-1.2 (m, 2H), 1.45 (s,9H), 1.65 (d, 2H), 1.75-1.9 (m, 2H), 2.45 (s, 3H), 2.55-2.75 (m, 2H)3.85 (d, 1H), 4.0-4.2 (br s, 2H), 7.35 (d, 2H), 7.8 (d, 2H); MassSpectrum [ESI]: (MNa)⁺=392.

EXAMPLE 2 Preparation of the hydrochloride salt of7-benzyloxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline (thehydrochloride salt of the compound of the Formula VI)

7-Benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (20.00 g) was mixedwith anisole (190 ml) and N,N-diisopropylethylamine (13.74 g). Thereaction mixture was inerted with nitrogen and cooled to 15° C.Phosphorus oxychloride (14.12 g) was charged to the reaction mixtureover a period of 15 minutes followed by anisole (10 ml) as a wash. Thereaction mixture was stirred for 15 minutes at 15° C. and then heated to80° C. over a period of 90 minutes. The reaction mixture was thenstirred at 80° C. for one hour. A solution of 4-bromo-2-fluoroaniline(16.8 g) in anisole (20 ml) was added to the reaction mixture over aperiod of 40 minutes. The reaction mixture was the stirred at 80° C. for90 minutes. The reaction mixture was then cooled to 25° C. and theproduct isolated by filtration. Yield: 26.9 g, 84%; NMR Spectrum(DMSOd₆, CD₃COOD) 4.0 (s, 3H), 5.37 (s, 2H), 7.35-7.5 (m, 4H), 7.52-7.62(m, 4H), 7.8 (d, 1H), 8.14 (s, 1H), 8.79 (s, 1H); Mass Spectrum [ESI](M+H)⁺=454.0591.

The 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one starting materialwas prepared as follows:

A mixture of vanillic acid (200 g), acetonitrile (600 ml) andN-ethyldiisopropylamine (580 ml) was heated to reflux. Benzyl bromide(347 ml) was then added over a period of 3 hours. The reaction mixturewas held at reflux for 15 hours. Triethylamine (50 ml) was added and thereaction mixture held at reflux for a further 30 minutes. Acetonitrile(400 ml) was added and the reaction mixture heated to 81° C. Water (300ml) was added and the reaction mixture cooled to 45° C. The reactionmixture was held at 45° C. for 30 minutes until crystallisationoccurred. The reaction mixture was then allowed to cool to 24° C. andthen further cooled to 8° C. and the product (benzyl4-(benzyloxy)-3-methoxybenzoate) isolated by filtration. The solid waswashed with water (3×500 ml) and then dried under vacuum at 45° C.Yield: 387 g, 93.4%; NMR Spectrum (CDCl₃) 3.9 (s, 3H), 5.2 (s, 2H), 5.3(s, 2H), 6.9 (d, 1H), 7.2-7.4 (m, 10H), 7.6-7.7 (m, 2H); Mass Spectrum(M+H)⁺=349.2.

Benzyl 4-(benzyloxy)-3-methoxybenzoate (78 g) was mixed withdichloromethane (580 ml), water (72 ml) and glacial acetic acid (288ml). The mixture was cooled to 10° C. Concentrated sulfuric acid (108ml) was added in a controlled manner maintaining the temperature of thereaction mixture below 25° C. Concentrated nitric acid (17.5 ml) wasthen added keeping the temperature of the reaction mixture below 20° C.The reaction mixture was then stirred at 20° C. for 23 hours. The loweraqueous layer was removed and the organic layer was washed with water(290 ml). The organic layer was separated and distilled to 270 ml atatmospheric pressure. Isopropanol (750 ml) was added to the reactionmixture at 45° C. The reaction mixture was then heated to 40° C. andstirred at this temperature for 15 minutes. The resulting suspension wasthen cooled to 20° C., then to 5° C. and held at this temperature forone hour. The product (benzyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate)was isolated by filtration, washed with isopropanol (200 ml) and driedat less than 25° C. Yield: 78.4 g, 89.6%; NMR Spectrum (CDCl₃) 3.9 (s,3H), 5.2 (s, 2H), 5.3 (s, 2H), 7.1 (s, 1H), 7.3-7.4 (m, 10H), 7.5 (s,1H); Mass Spectrum (M+H)⁺=394.1.

Benzyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (77 g) was dissolved inacetonitrile (882 ml). Sodium dithionite (160.5 g) was added to thesolution and the temperature adjusted to 25° C. Water (588 ml) was thenadded, maintaining the temperature at 25° C. The pH was maintained at 6using 8.8 M sodium hydroxide during the reduction. The slurry was thenheated to 65° C. and the lower aqueous phase was removed. Concentratedhydrochloric acid (35% w/w, 7.25 ml) was then added. The slurry wasallowed to cool to 40° C. and then to 20° C. Sodium hydroxide solution(47% w/w, 12.4 ml) was added and the slurry cooled to 0° C. The product(benzyl 2-amino-4-(benzyloxy)-5-methoxybenzoate) was isolated byfiltration, washed with water (2×196 ml) and then dried at 40° C. undervacuum. Yield: 66.2 g, 92.4%; NMR Spectrum (CDCl₃) 3.8 (s, 3H), 5.1 (s,2H), 5.3 (s, 2H), 6.2 (s, 1H), 7.3-7.4 (m, 10H); Mass Spectrum(M+H)⁺=364.1.

Benzyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (5.55 kg), formamidineacetate (2.2 kg) and isobutanol (33.3 L) were mixed. The reactionmixture was then heated to 97° C. and stirred at this temperature for 6hours. The reaction mixture was then cooled to 25° C. over a period ofat least an hour and then stirred at this temperature for 30 minutes.The product (7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one) wasisolated by filtration, washed with isobutanol (6.1 L) and dried in thevacuum oven at a temperature of from 40 to 45° C. Yield: 4.25 kg, 98%;NMR Spectrum (DMSOd₆) 3.9 (s, 3H), 5.3 (s, 2H), 7.3 (s, 1H), 7.3-7.5 (m,6H), 8.0 (s, 1H); Mass Spectrum (M+H)⁺=283.1.

The 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one starting materialwas additionally prepared as follows:

A mixture of vanillic acid (20 g), acetonitrile (60 ml) andN-ethyldiisopropylamine (58 ml) was heated to reflux. Benzyl bromide(34.7 ml) was then added within 15 minutes. The reaction mixture washeld at reflux for about 10 hours. Triethylamine (5 ml) was added andthe reaction mixture held at reflux for a further 30 minutes.Acetonitrile (40 ml) and water (30 ml) were added and the reactionmixture cooled to 45° C. The reaction mixture was held at 45° C. untilcrystallisation occurred. The reaction mixture was then allowed to coolto 24° C. and then further cooled to 8° C. and the product (benzyl4-(benzyloxy)-3-methoxybenzoate) isolated by filtration. The solid waswashed with water (3×50 ml) and then dried under vacuum at 45° C. Yield:38.7 g, 93%; NMR Spectrum (CDCl₃) 3.9 (s, 3H), 5.2 (s, 2H), 5.3 (s, 2H),6.9 (d, 1H), 7.2-7.4 (m, 10H), 7.6-7.7 (m, 2H); Mass Spectrum(M+H)⁺=349.2.

Benzyl 4-(benzyloxy)-3-methoxybenzoate (135 g) was dissolved indichloromethane (339 ml). Glacial acetic acid (175.5 g) was added andthe mixture cooled to 10° C. Concentrated sulfuric acid (151.6 g) wasadded in a controlled manner maintaining the temperature of the reactionmixture below 25° C. Concentrated nitric acid (61.6 g) was then added in15 minutes keeping the temperature of the reaction mixture below 25° C.The reaction mixture was then heated to 40° C. and stirred for 3 hours.The lower aqueous layer was removed and the organic layer was washedtwice with water (2×168 ml). The organic layer was distilled to atatmospheric pressure to remove dichloromethane (186 ml). Isopropanol(339 ml) was added to the reaction mixture at 40° C. The reactionmixture was held at 40° C. for 15 minutes. The resulting suspension wasthen cooled to 20° C. within 30 minutes, then to 5° C. and held at thistemperature for one hour. The product (benzyl4-(benzyloxy)-5-methoxy-2-nitrobenzoate) was isolated by filtration,washed with isopropanol (336 ml) and dried at less than 25° C. Yield:135.7 g, 89.6%; NMR Spectrum (CDCl₃) 3.9 (s, 3H), 5.2 (s, 2H), 5.3 (s,2H), 7.1 (s, 1H), 7.3-7.4 (m, 10H), 7.5 (s, 1H); Mass Spectrum(M+H)⁺=394.1.

Benzyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (90 g) was charged toacetonitrile (660 g). 85% Sodium dithionite (75 g) was added to thesolution and the temperature adjusted to 20° C. Water (516 g) was thenadded, maintaining the temperature at 20° C. The slurry was then heatedto 65° C. and stirred for 30 minutes. Sodium dithionite (75 g) was addedand the mixture stirred for another 30 minutes. The lower aqueous phasewas removed. Concentrated hydrochloric acid (33% w/w, 12.48 g) was thenadded to adjust to a pH of <1. The suspension is held for 1 hour. Theslurry was cooled to 20° C. over 30 minutes. Sodium hydroxide solution(20% w/w, 59.29 g) was added to give a pH of 10. The slurry was cooledto 0° C. and stirred for one hour. The product (benzyl2-amino-4-(benzyloxy)-5-methoxybenzoate) was isolated by filtration,washed twice with water (2×222 ml) and then dried at 60° C. undervacuum. Yield: 78.81 g, 95%; NMR Spectrum (CDCl₃) 3.8 (s, 3H), 5.1 (s,2H), 5.3 (s, 2H), 6.2 (s, 1H), 7.3-7.4 (m, 10H); Mass Spectrum(M+H)⁺=364.1.

Benzyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (80.0 g), formamidineacetate (32.0 g) and isobutanol (480 ml) were mixed. The reactionmixture was then heated to 97° C. and stirred at this temperature for 6hours. The reaction mixture was then cooled to 25° C. over a period ofat least an hour and then stirred at this temperature for 30 minutes.The product (7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one) wasisolated by filtration, washed with isobutanol (64.2 g) and dried in thevacuum oven at a temperature of from 40 to 45° C. Yield: 60.8 g, 98%;NMR Spectrum (DMSOd₆) 3.9 (s, 3H), 5.3 (s, 2H), 7.3 (s, 1H), 7.3-7.5 (m,6H), 8.0 (s, 1H); Mass Spectrum (M+H)⁺=283.1.

EXAMPLE 3 Preparation of the hydrochloride salt of7-benzyloxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline (thehydrochloride salt of the compound of the Formula VI)

7-Benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (20.00 g) was mixedwith toluene (190 ml) and N,N-diisopropylethylamine (13.74 g). Thereaction mixture was inerted with nitrogen and cooled to 15° C.Phosphorus oxychloride (19.8 g) was charged to the reaction mixture overa period of 15 minutes, followed by toluene (10 ml) as a wash. Thereaction mixture was stirred for 15 minutes at 15° C. and then heated to80° C. over a period of 90 minutes. The reaction mixture was thenstirred at 80° C. for two hours. A solution of 4-bromo-2-fluoroaniline(16.8 g) in toluene (40 ml) was added to the reaction mixture over aperiod of 40 minutes, followed by toluene (10 ml) as a wash. Thereaction mixture was then stirred at 80° C. for 4 hours. The reactionmixture was then cooled to 25° C. and the product isolated byfiltration. The filter cake was washed twice with water (2×40 ml).Yield: 34.37 g, 87%; NMR Spectrum (DMSOd₆, CD₃COOD) 4.0 (s, 3H), 5.37(s, 2H), 7.35-7.5 (m, 4H), 7.52-7.62 (m, 4H), 7.8 (d, 1H), 8.14 (s, 1H),8.79 (s, 1H); Mass Spectrum [ESI] (M+H)⁺=454.0591.

EXAMPLE 4 Preparation of trifluoroacetic acid salt of7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline (thetrifluoroacetic acid salt of the compound of the Formula IX)

7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (100 g), triethylamine(59.3 ml) and toluene (650 ml) were charged to a vessel and inerted withnitrogen. The contents were heated to 40° C. and charged over a periodof about 40 minutes to a solution of phosphorus oxychloride (97.7 g) intoluene (400 ml) held at 73° C. in a vessel inerted with nitrogen. Thereaction mixture was then held at a temperature of about 73° C. for aperiod of about 90 minutes. 4-Bromo-2-fluoroaniline (84.1 g) wasdissolved in toluene (250 ml) and charged to the reaction mixture at 73°C. and held stirring at this temperature for about 4 hours.Trifluoroacetic acid (350 ml) was then added to the reaction mixture at73° C. and the reaction mixture stirred at 73° C. for 6 hours and thencooled to 60° C. Water (1750 ml) was added to the reaction mixture andthe temperature held at 60° C. for about 30 minutes and then warmed to70° C. and stirred at 70° C. for about 22 hours. The reaction mixturewas then cooled to 20° C. and the product isolated by filtration, washedwith water (200 ml) and dried at 50° C. Yield: 120 g, 93%; NMR Spectrum(DMSOd₆) 4.0 (s, 3H), 7.24 (s, 1H), 7.56 (m, 2H), 7.78 (d, 1H), 8.02 (s,1H), 8.73 (s, 1H); Mass Spectrum (M+H)⁺=454.0591.

EXAMPLE 5 Preparation of trifluoroacetic acid salt of7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline (thetrifluoroacetic acid salt of the compound of the Formula IX)

7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (15 g), triethylamine(9.0 ml) and toluene (90 ml) were charged to a vessel and inerted withnitrogen. The contents were held at ambient and charged over a period ofabout 40 minutes to a solution of phosphorus oxychloride (14.7 g) intoluene (60 ml) held at 73° C. in a vessel inerted with nitrogen. Thiswas followed by a toluene (7.5 ml) line wash. The reaction mixture wasthen held at a temperature of about 73° C. for a period of about 90minutes. 4-Bromo-2-fluoroaniline (12.6 g) was dissolved in toluene (30ml) and charged to the reaction mixture at 73° C. and held stirring atthis temperature for about 4 hours. Trifluoroacetic acid (60 ml) wasthen added to the reaction mixture at 73° C. and the reaction mixturestirred at 73° C. for 6 hours and then cooled to 60° C. Potassiumhydroxide (48-50% w/w, 16.1 ml) in water (10.5 ml) was charge overapproximately 30 minutes followed by a hour hold at 60° C. Water (180ml) was added to the reaction mixture over approximately 70 minutesfollowed by 7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazolinetrifluoroacetic acid salt seed (0.13 g). The batch was held at 60° C.for about 60 minutes and then water (60 ml) was added over approximately20 minutes. The reaction mixture was held for approximately two hoursthen cooled to 20° C. and the product isolated by filtration, washedwith toluene (50 ml) and methanol/water (1:10, 50 ml) and dried at 50°C. Yield: 22 g, 89%; NMR Spectrum (DMSOd₆) 4.0 (s, 3H), 7.24 (s, 1H),7.56 (m, 2H), 7.78 (d, 1H), 8.02 (s, 1H), 8.73 (s, 1H); Mass Spectrum(M+H)⁺=454.0591.

EXAMPLE 6 Preparation of a hydrogen chloride salt of7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline (the hydrogenchloride salt of the compound of the Formula IX)

7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (30.00 g) was mixedwith triethylamine hydrochloride (2.99 g), anisole (285 ml) andN,N-diisopropylethylamine (20.71 g). The reaction mixture was inertedwith nitrogen and cooled to 15° C. Phosphorus oxychloride (21.4 g) wasadded to the reaction mixture over a period of 15 minutes followed by ananisole (30 ml) wash. The reaction mixture was then stirred for 15minutes at 15° C. and then heated to 80° C. over a period of 90 minutes.The reaction mixture was stirred at 80° C. for one hour. A solution of4-bromo-2-fluoroaniline (25.2 g) in anisole (15 ml) was added to thereaction mixture over a period of 25 minutes. The reaction mixture wasstirred for 4 hours at 80° C. Aqueous hydrogen chloride (35% w/w, 122ml) and acetic acid (198 ml) were charged to the reaction mixture. Thereaction mixture was stirred for 3 hours and then the anisole layer wasremoved. The reaction mixture was cooled to 25° C. and the solidisolated by filtration. Yield: 13.9 g, 54%; NMR Spectrum (DMSOd₆) 4.0(s, 3H), 7.43 (s, 1H), 7.5 (m, 2H), 7.7 (d, 1H), 8.37 (s, 1H), 8.72 (s,1H); Mass Spectrum (M+H)⁺=454.0591.

EXAMPLE 7 Preparation of hydrogen chloride salt of7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline (the hydrogenchloride salt of the compound of the Formula IX)

Phosphorus oxychloride (6.0 ml) was added over a period of 60 minutes toa stirred slurry of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one(10.0 g) and N,N-diisopropylethylamine (7.45 ml) in toluene (105 ml) at20° C. After stirring the reaction mixture for 30 minutes at 20° C., thereaction mixture was heated over a period of 90 minutes to 73° C. andthen stirred for a further 3 hours at that temperature.4-bromo-2-fluoroaniline (8.4 g) in toluene (20 ml) was added to thereaction mixture at 73° C., followed by a toluene wash (5 ml).Trifluoroacetic acid (35 ml, 3.5 vol) was added over a period of 10minutes to the reaction mixture at 73° C. and the reaction mixture wasthen stirred at that temperature for 5 hours. The reaction mixture wasthen cooled to 60° C. and water (175 ml) was added over a period of 15minutes. The reaction mixture was then warmed to 68° C. and stirred atthat temperature for 8 hours. The reaction mixture was then cooled to20° C. over a period of 1 hour and the product was filtered off andwashed with water (20 ml). Yield: 11.56 g, 90%; NMR Spectrum (DMSOd₆)4.0 (s, 3H), 7.43 (s, 1H), 7.5 (m, 2H), 7.7 (d, 1H), 8.37 (s, 1H), 8.72(s, 1H); Mass Spectrum (M+H)⁺=454.0591.

EXAMPLE 8 Preparation of trifluoroacetic acid salt of7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline (thetrifluoroacetic acid salt of the compound of the Formula IX)

Phosphorus oxychloride (6.0 ml) was added over a period of 15 minutes toa stirred slurry of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one(10.0 g) and triethylamine (5.9 ml) in toluene (105 ml) at 73° C. andthe reaction mixture stirred for a further 3 hours.4-bromo-2-fluoroaniline (8.4 g) in toluene (20 ml) was added to thereaction mixture at 73° C., followed by a toluene wash (5 ml).Trifluoroacetic acid (35 ml, 3.5 vol) was then added over a period of 10minutes to the reaction mixture at 73° C. and the reaction mixture wasthen stirred at that temperature for a further 5 hours. The reactionmixture was cooled to 60° C. and water (175 ml) was added over a periodof 15 minutes. The reaction mixture was then warmed to 68° C. andstirred at that temperature for 8 hours. The slurry was cooled to 20° C.over 1 hour and the product was filtered off and washed with water (20ml). Yield: 11.24 g, 87%; NMR Spectrum (DMSOd₆) 8.72 (1H, s), 8.02 (1H,s), 7.76-7.73 (1H, m), 7.56-7.50 (2H, m), 7.25 (1H, s), 3.97 (3H, s);Mass Spectrum (M+H)⁺=454.0591.

EXAMPLE 9 Preparation of7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline(the compound of the Formula X)

7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline (100 g) andpotassium carbonate (113.8 g) were suspended in N-methylpyrrolidinone(1070 ml) and stirred for 10 minutes prior to the addition of1-(tert-butoxycarbonyl)-4-(4-methylphenylsulfonyloxymethyl)piperidine(152.2 g). The reaction mixture was then heated to 95° C. for 4 hoursbefore being cooled back to 70° C. Water (1922 ml) was then added over aperiod of 15 minutes. The reaction mixture was held at 73° C. for 1 hourbefore being cooled to 40° C. and the product isolated by filtration.The product was washed with water (549 ml), slurry washed with ethylacetate (549 ml) at 50° C. for 1 hour and then washed with ethyl acetate(275 ml) and dried at 50° C. Yield: 137 g, 86%; NMR Spectrum (DMSOd₆)1.15-1.3 (m, 2H), 1.46 (s, 9H), 1.8 (d, 2H), 2.0-2.1 (m, 1H), 2.65-2.9(m, 2H) 3.95 (s, 3H), 4.02 (br s, 2H), 4.05 (d, 2H), 7.2 (s, 1H), 7.48(d, 1H), 7.55 (t, 1H), 7.65 (d, 1H), 7.8 (d, 1H), 8.35 (s, 1H), 9.55 (brs, 1H); Mass Spectrum [ESI] (M+H)⁺=561-563.

EXAMPLE 10 Preparation of7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline(the compound of the Formula X)

7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline (5.0 g) andpotassium carbonate (5.7 g) were suspended in N-methylpyrrolidinone(53.5 ml) and stirred for 10 minutes.1-(tert-butoxycarbonyl)-4-(4-methylphenylsulfonyloxymethyl)piperidine(7.6 g) was then added. The reaction mixture was then heated to 95° C.and stirred at that temperature for 3.5 hours before being cooled backto 70° C. Isopropanol (25 ml) was added and then water (75 ml) was addedover a period of 15 minutes. The reaction mixture was then stirred at73° C. for 1 hour before cooling to 40° C. and isolation of the productby filtration. The product was washed with water (27.4 ml) and dried at50° C. Yield: 6.72 g, 87.2%; NMR Spectrum (DMSOd₆) 1.15-1.3 (m, 2H),1.46 (s, 9H), 1.8 (d, 2H), 2.0-2.1 (m, 1H), 2.65-2.9 (m, 2H) 3.95 (s,3H), 4.02 (br s, 2H), 4.05 (d, 2H), 7.2 (s, 1H), 7.48 (d, 1H), 7.55 (t,1H), 7.65 (d, 1H), 7.8 (d, 1H), 8.35 (s, 1H), 9.55 (br s, 1H); MassSpectrum [ESI] (M+H)⁺=561-563.

EXAMPLE 11 Preparation of7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline(the compound of the Formula X)

7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline (9.7 g),sodium hydroxide (47% w/w, 5.0 ml) and Adogen® 464 (1.5 g) were added towater (50 ml) with stirring.1-(tert-butoxycarbonyl)-4-(4-methylphenylsulfonyloxymethyl)piperidine(10.0 g) as a solution in toluene (35 ml) was then added to the reactionmixture and heated to 70° C. for 18 hours. The reaction mixture was thencooled to 20° C. and the product was isolated by filtration. The productwas then washed with toluene (20 ml) and dried at 50° C. Yield: 8.72 g,77%; NMR Spectrum (DMSOd₆) 1.15-1.3 (m, 2H), 1.46 (s, 9H), 1.8 (d, 2H),2.0-2.1 (m, 1H), 2.65-2.9 (m, 2H) 3.95 (s, 3H), 4.02 (br s, 2H), 4.05(d, 2H), 7.2 (s, 1H), 7.48 (d, 1H), 7.55 (t, 1H), 7.65 (d, 1H), 7.8 (d,1H), 8.35 (s, 1H), 9.55 (br s, 1H); Mass Spectrum [ESI] (M+H)⁺=561-563.

EXAMPLE 12 Preparation of4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(ZD6474)

7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline(100 g), water (80 ml), formic acid (120 ml) and aqueous formaldehyde(38% w/w, 28.2 g) were added to a vessel equipped with overhead stirrer,reflux condenser and purged with nitrogen. The reaction mixture washeated to 80° C. over a period of 90 minutes and stirred at thistemperature for 5 hours. The reaction mixture was then cooled to 20° C.and tetrahydrofuran (500 ml) was added. The reaction mixture was warmedto 40° C. and sodium hydroxide (47% w/w, 265 ml) was added, followed bywater (60 ml). The aqueous phase was separated and discarded. Theorganic phase was adjusted to 60° C. and water (300 ml) and butylacetate (300 ml) were added. The resulting mixture was stirred at 60° C.for 15 minutes and then the aqueous phase separated and discarded. Water(400 ml) was then added to the organic phase, which was stirred at 60°C. for 15 minutes and then the aqueous phase separated and discarded.Butyl acetate (300 ml) and tetrahydrofuran (50 ml) were added to theorganic phase and set for distillation at ambient pressure. Thedistillation was stopped when the contents temperature reached 104° C.The slurry was then cooled to 20° C. and held for 2 hours beforeisolating the product by filtration. The product was washed with butylacetate (300 ml) and dried at 50° C. Yield: 76.7 g, 90.6%; NMR Spectrum(pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2.76 (2H,m), 3.63 (3H, s), 3.97 (2H, d), 7.38 (1H, ddd), 7.49 (1H, dd), 7.64 (1H,s), 7.88 (1H, t), 7.89 (1H, s), 9.01 (1H, s), 10.37 (1H, s); MassSpectrum (M+H)⁺=475.

EXAMPLE 13 Preparation of4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(ZD6474)

7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline(35.0 g), water (28 ml), formic acid (42 ml) and aqueous formaldehyde(37% w/w, 8.2 g) were added to a vessel equipped with overhead stirrer,reflux condenser and purged with nitrogen. The reaction mixture washeated to 80° C. and stirred at this temperature for 5 hours. Thereaction mixture was then cooled to 40° C. and tetrahydrofuran (175 ml)was added. Sodium hydroxide (47% w/w, 61.9 ml) was added at 40° C.followed by water (21 ml). The aqueous phase was then separated anddiscarded. Water (420 ml) was added to the organic phase at 40° C. overa period of 30 minutes. The slurry was then cooled to 20° C. beforeisolating the product by filtration. The product was washed with water(175 ml) and dried at 50° C. Yield: 27.1 g, 91.4%; NMR Spectrum(pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2.76 (2H,m), 3.63 (3H, s), 3.97 (2H, d), 7.38 (1H, ddd), 7.49 (1H, dd), 7.64 (1H,s), 7.88 (1H, t), 7.89 (1H, s), 9.01 (1H, s), 10.37 (1H, s); MassSpectrum (M+H)⁺=475.

EXAMPLE 14 Preparation of4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(ZD6474)

7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline(100 g), water (80 ml), formic acid (120 ml) and aqueous formaldehyde(37% w/w, 26.7 g) were added to a vessel equipped with overhead stirrer,reflux condenser and purged with nitrogen. The reaction mixture washeated to 80° C. over a period of 90 minutes and stirred at thistemperature for 5 hours. The reaction mixture was then cooled to 60° C.and methanol (800 ml) was added, followed by potassium hydroxide (49%w/w, 228 ml) over 2 hours. The slurry was cooled to 20° C. over 2 hoursbefore isolating the product by filtration. The product was washed twicewith aqueous methanol (2:1 methanol:water, 300 ml) and dried at 50° C.Yield: 79.6 g, 94%; NMR Spectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90(5H, m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H, s), 3.97 (2H, d), 7.38(1H, ddd), 7.49 (1H, dd), 7.64 (1H, s), 7.88 (1H, t), 7.89 (1H, s), 9.01(1H, s), 10.37 (1H, s); Mass Spectrum (M+H)⁺=475.

EXAMPLE 15 Preparation of4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(ZD6474)

7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline(100 g), water (45 ml), formic acid (120 ml) and aqueous formaldehyde(37% w/w, 101.8 g) were added to a vessel equipped with an overheadstirrer and a reflux condenser and purged with nitrogen. The reactionmixture was heated to 80° C. over a period of 90 minutes and stirred atthis temperature for 5 hours. The reaction mixture was then cooled to60° C. and methanol (800 ml) was added, followed by potassium hydroxide(49% w/w, 228 ml) over 2 hours. The slurry was cooled to 20° C. over 2hours before isolating the product by filtration. The product was washedtwice with aqueous methanol (2:1 methanol:water, 300 ml) and dried at50° C. Yield: 79.6 g, 94%; NMR Spectrum (pyridine-d5) 1.49 (2H, m),1.75-1.90 (5H, m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H, s), 3.97 (2H,d), 7.38 (1H, ddd), 7.49 (1H, dd), 7.64 (1H, s), 7.88 (1H, t), 7.89 (1H,s), 9.01 (1H, s), 10.37 (1H, s); Mass Spectrum (M+H)⁺=475.

EXAMPLE 16 Preparation of4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(ZD6474)

7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline(36 g @ 100% w/w), water (16 ml), formic acid (44 ml) and aqueousformaldehyde (37% w/w, 36.4 g) were added to a vessel equipped with anoverhead stirrer and a reflux condenser and purged with nitrogen. Thereaction mixture was heated to 80° C. over a period of 90 minutes andstirred at this temperature for 7 hours. The reaction mixture was thencooled to 60° C. and methanol (376 ml) was added, followed by potassiumhydroxide (49% w/w, 86 ml) over 2 hours. The slurry was seeded withZD6474 (methanolate form, 300 mg) and cooled to 20° C. over 2 hoursbefore isolating the product by filtration. The product was washed twicewith aqueous methanol (80:20 methanol:water, 67 ml) and dried at ambienttemperature. Yield: 32.4 g, 95%; NMR Spectrum (pyridine-d5) 1.49 (2H,m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H, s), 3.97(2H, d), 7.38 (1H, ddd), 7.49 (1H, dd), 7.64 (1H, s), 7.88 (1H, t), 7.89(1H, s), 9.01 (1H, s), 10.37 (1H, s); Mass Spectrum (M+H)⁺=475.

EXAMPLE 17 Purification of4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(ZD6474)

4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazolineprepared as described in Example 9 (100 g) was suspended intetrahydrofuran (500 ml), water (250 ml) and butyl acetate (400 ml) andheated to reflux to allow dissolution. The mixture was then cooled to60° C. and the aqueous phase separated and discarded. The organic phasewas filtered. Tetrahydrofuran (50 ml) and butyl acetate (600 ml) wereadded to the organic filtrates and then heated to distil at ambientpressure until an internal temperature of 106° C. was reached. Theslurry was then cooled to 5° C., filtered and washed with ethyl acetate(200 ml). The product was dried at 50° C. Yield: 91.8 g, 91.8%; NMRSpectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.15 (3H, s),2.76 (2H, m), 3.63 (3H, s), 3.97 (2H, d), 7.38 (1H, ddd), 7.49 (1H, dd),7.64 (1H, s), 7.88 (1H, t), 7.89 (1H, s), 9.01 (1H, s), 10.37 (1H, s);Mass Spectrum (M+H)⁺=475.

EXAMPLE 18 Preparation of4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(ZD6474)

7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline(40 g), water (16 ml), formic acid (43 ml) and aqueous formaldehyde (37%w/w, 33 ml) were added to a vessel equipped with overhead stirrer,reflux condenser and thermometer. The reaction mixture was heated to 81°C. and stirred at this temperature for 5 hours. The reaction mixture wascooled to 60° C. and tetrahydrofuran (178 ml) was added. The temperatureof the reaction mixture was adjusted to 40° C. and potassium hydroxide(49% w/w, 84 ml) was added, followed by water (22 ml). The aqueous phasewas separated and discarded. The organic phase was adjusted to 60° C.and water (107 ml) and butyl acetate (107 ml) were added. The aqueousphase was separated and discarded. The organic phase was filtered,following through with tetrahydrofuran (18 ml) wash. The temperature ofthe filtrates was adjusted to 60° C. and butyl acetate (107 ml) wasadded. The reaction mixture was set for distillation at ambientpressure. The distillation was stopped when the contents temperaturereached 106° C. The slurry was cooled to 65° C. and tetrahydrofuran (107ml) was added. The slurry was cooled to 0-5° C. and held for 1 hourbefore isolating the product by filtration. The product was washed withethyl acetate (72 ml) and dried at 50° C. Yield: 24.82 g, 80.3%.

EXAMPLE 19 X-Ray Powder Diffraction of Anhydrous ZD6474

The processes of the present invention synthesize the anhydrous from ofZD6474. The anhydrous form of ZD6474 is characterised by X-Ray powderdiffraction and is characterised in providing at least one of thefollowing 2 theta values measured using CuKα radiation: 15.0° and 21.4°.The anhydrous form of ZD6474 is characterised in providing a CuKα X-raypowder diffraction pattern as shown in FIG. 1. The ten most prominentpeaks are shown in Table 1.

TABLE 1 Ten most prominent X-Ray Powder Diffraction peaks for theanhydrous form of ZD6474 Angle 2- Intensity Relative Theta (°2θ) CountIntensity 15.0 100 vs 21.4 92.8 vs 23.3 63.7 vs 20.7 48.3 vs 18.9 40.4vs 18.1 40.1 vs 23.7 39.2 vs 8.3 28.9 vs 22.1 25.9 vs 29.5 23.2 s vs =very strong; s = strong

TABLE 2 % Relative Intensity* Definition 25-100 vs (very strong) 10-25 s (strong)    3-10 m (medium)   1-3  w (weak)    *The relativeintensities are derived from diffractograms measured with fixed slits.Analytical Instrument: Siemens D5000, calibrated using quartz.The X-ray powder diffraction spectra is determined by mounting a sampleof the crystalline ZD6474 material on Siemens single silicon crystal(SSC) wafer mounts and spreading out the sample into a thin layer withthe aid of a microscope slide. The sample is spun at 30 revolutions perminute (to improve counting statistics) and is irradiated with X-raysgenerated by a copper long-fine focus tube operated at 40 kV and 40 mAusing CuKα radiation with a wavelength of 1.5406 angstroms. Thecollimated X-ray source is passed through an automatic variabledivergence slit set at V20 and the reflected radiation is directedthrough a 2 mm antiscatter slit and a 0.2 mm detector slit. The sampleis exposed for 1 second per 0.02 degree 2-theta increment (continuousscan mode) over the range 2 degrees to 40 degrees 2-theta in theta-thetamode. The running time is 31 minutes and 41 seconds. The instrument isequipped with a scintillation counter as detector. Control and datacapture is by means of a Dell Optiplex 686 NT 4.0 Workstation operatingwith Diffract+ software. Persons skilled in the art of X-ray powderdiffraction will realise that the relative intensity of peaks can beaffected by, for example, grains above 30 microns in size andnon-unitary aspect ratios which may affect analysis of samples. Theskilled person will also realise that the position of reflections can beaffected by the precise height at which the sample sits in thediffiactometer and the zero calibration of the diffiactometer. Thesurface planarity of the sample may also have a small effect. Hence thediffraction pattern data presented are not to be taken as absolutevalues.

For more information on X-ray powder diffraction the reader is referredto Jenkins, R & Snyder, R. L. ‘Introduction to X-Ray PowderDiffractometry’ John Wiley & Sons 1996; Bunn, C. W. (1948), ChemicalCrystallography, Clarendon Press, London; Klug, H. P. & Alexander, L. E.(1974), X-Ray Diffraction Procedures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: X-Ray Powder Diffraction Pattern for ZD6474 anhydrous—with the 2theta values plotted on the horizontal axis and the relative lineintensity (counts) plotted on the vertical axis.

1.-13. (canceled)
 14. A process for the manufacture of7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline, a compoundof the Formula IX:

from a compound of the Formula VII:

wherein R¹ is an acid labile protecting group, which process comprisesconverting the compound of the Formula VII to a compound of the FormulaVI:

by the steps of: (g) reacting the compound of the Formula VII with asuitable chlorinating agent in the presence of a suitable base and asolvent selected from the group consisting of an aryl alkyl ether, adialkyl ether, a halo substituted benzene and an alkyl substitutedbenzene, wherein the reaction is carried out by: (g-1) adding a mixtureof the compound of the Formula VII and the base in the solvent to amixture of the chlorinating agent in the solvent at a temperature in therange of from 60 to 90° C. over a period of about 60 minutes; or (g-2)adding the chlorinating agent to a mixture of the compound of theFormula VII and the base in the solvent at ambient temperature over aperiod of about 15 minutes and then heating the reaction mixture over aperiod of about 90 minutes to a temperature in the range of from 70 to90° C. and stirring the reaction mixture at that temperature for about 1hour; or (g-3) adding the chlorinating agent to a mixture of thecompound of the Formula VII and the base in the solvent at a temperaturein the range of from 60 to 110° C. over a period of about 15 minutes, toform a compound of the Formula VIII:

and (h) reacting the compound of the Formula VIII with4-bromo-2-fluoroaniline in situ in the presence of the solvent used instep (g) to form the compound of the Formula VI as a hydrochloride salt;(j) removing R¹ from the compound of the Formula VI in situ in thepresence of the solvent used in steps (g) and (h) to form the compoundof the Formula IX or a salt thereof; and whereafter the compound of theFormula IX obtained in the form of the free base may optionally beconverted into a pharmaceutically acceptable salt.
 15. The processaccording to claim 14, wherein R¹ is benzyl and in step (j) the benzylgroup is removed in situ by reaction with trifluoroacetic acid at atemperature in the range of from 60 to 80° C.
 16. The process accordingto claim 14 wherein R¹ is benzyl and the benzyl group is removed in thepresence of trifluoroacetic acid and the compound of Formula IX isconverted into a trifluoroacetic acid salt by addition of potassiumhydroxide or sodium hydroxide.
 17. A process for the manufacture of7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline, a compoundof the Formula IX:

from a compound of the Formula VII:

which process comprises converting the compound of the Formula VII to acompound of the Formula VI:

by conducting a process according to claim 14 and further including astep (i) of isolating the compound of the Formula VI; and (k) removingR¹ from the compound of the Formula VI to form the compound of theFormula IX or a salt thereof; and whereafter the compound of the FormulaIX obtained in the form of the free base may optionally be convertedinto a pharmaceutically acceptable salt.
 18. The process according toclaim 17, wherein R¹ is benzyl and in step (k) the benzyl group isremoved by reaction with a suitable hydrogenation agent.
 19. A processfor the manufacture of7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline,a compound of the Formula X:

from a compound of the Formula VII:

which process comprises converting the compound of the Formula VII to acompound of the Formula IX:

by conducting a process according to claim 14; and (l) reacting thecompound of the Formula IX with a compound of the Formula II:

in the presence of a suitable base to provide a compound of the FormulaX or a salt thereof; and whereafter the compound of the Formula Xobtained in the form of the free base may optionally be converted into apharmaceutically acceptable salt.
 20. The process according to claim 19,wherein the base used in step (l) is selected from the group consistingof sodium carbonate, potassium carbonate, sodium hydroxide and potassiumhydroxide.
 21. The process according to claim 19, further including astep (m) of isolating the compound of the Formula X.
 22. A process forthe manufacture of7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline,a compound of the Formula X:

from 7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline, acompound of the Formula IX:

which process comprises: (l) reacting the compound of the Formula IXwith a compound of the Formula II:

in the presence of a suitable base to provide a compound of the FormulaX or a salt thereof; and (m) isolating the compound of the Formula X by:(m-1) adding water and allowing crystallization of the compound of theFormula X to occur, collecting the compound of the Formula X and washingthe compound of the Formula X with water, followed by a solvent selectedfrom the group consisting of ethyl acetate, butyl acetate andacetonitrile at a temperature in the range of from 25 to 55° C.; or(m-2) adding water and an alcohol selected from the group consisting ofmethanol, ethanol, isopropanol and n-propanol and allowingcrystallization of the compound of the Formula X to occur, collectingthe compound of the Formula X and washing the compound of the Formula Xwith a mixture of water and the alcohol selected from the groupconsisting of methanol, ethanol, isopropanol and n-propanol, followed bya solvent selected from the group consisting of ethyl acetate, butylacetate and acetonitrile at a temperature in the range of from 25 to 55°C.; and whereafter the compound of the Formula X obtained in the form ofthe free base may optionally be converted into a pharmaceuticallyacceptable salt.
 23. The process according to claim 22, wherein the baseused in step (l) is selected from the group consisting of sodiumcarbonate and potassium carbonate.
 24. The process according to claim19, wherein the compound of the Formula II used in step (l) is preparedfrom a (C1-C6)alkyl-4-piperidinecarboxylate compound of the Formula III:

by the steps of: (a) reacting the (C1-C6)alkyl-4-piperidinecarboxylatecompound of the Formula III with di-tert-butyl dicarbonate in thepresence of toluene or xylene to form a first mixture comprising tolueneor xylene, tert-butanol and a compound of the Formula IV:

(b) substantially removing the tert-butanol from the first mixture; (c)reacting the compound of the Formula IV with a suitable reducing agentin situ in the presence of toluene or xylene to form a second mixturecomprising a compound of the Formula V:

(d) substantially removing alcohol by-products formed in step (c) fromthe second mixture; and (e) reacting the compound of the Formula V withtosyl chloride in situ to form the compound of the Formula II in thepresence of a suitable base and toluene. 25.-30. (canceled)